Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients

ABSTRACT

Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients, are provided. Certain of the systems and methods described herein are capable of manufacturing multiple chemical products without the need to fluidically connect or disconnect unit operations when switching from one making chemical product to making another chemical product.

RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.15/504,049, filed Feb. 15, 2017, which is a National Stage Applicationunder 35 U.S.C. § 371 of International Patent Application No.PCT/US2015/045220, filed on Aug. 14, 2015, which claims priority under35 U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 62/038,039,filed Aug. 15, 2014, each of which is incorporated herein by referencein its entirety for all purposes.

GOVERNMENT SPONSORSHIP

This invention was made with government support under Contract No.N66001-11-C-4147 awarded by the Space and Naval Warfare Systems Center.The government has certain rights in the invention.

TECHNICAL FIELD

Systems and methods for synthesizing chemical products, including activepharmaceutical ingredients are generally described.

BACKGROUND

Recently, pharmaceutical and biotechnology industries have experiencedperiods of slowed growth and increased costs associated with thedevelopment of new chemical products and active pharmaceuticalingredients. While individual processes involved in certainpharmaceutical manufacturing are transitioning to continuous-likeprocesses, pharmaceutical facilities generally still rely on batch orsemi-batch techniques to produce complex chemical products. Currentprocesses are typically tailored to manufacture a single specific activepharmaceutical ingredient and generally require large, expensive, andstatic setups. While continuous processes are suggested to offernumerous benefits, including reduced cost, complete infrastructure andsystems capable of complex continuous manufacturing of chemical productsand active pharmaceutical ingredients do not exist. The ability tosynthesize and formulate chemical products (and, in some cases, multiplechemical products) in a single continuous, self-contained, systemremains elusive.

SUMMARY

Systems and methods for synthesizing chemical products, including activepharmaceutical ingredients, are provided. Certain of the systems andmethods described herein are capable of manufacturing multiple chemicalproducts without the need to fluidically connect or disconnect unitoperations when switching from one making chemical product to makinganother chemical product. The subject matter of the present inventioninvolves, in some cases, interrelated products, alternative solutions toparticular problem, and/or a plurality of different uses of one or moresystems and/or articles.

In one aspect, a system for producing a chemical product is provided.The system can comprise, in some embodiments, a first module comprisinga first unit operation, a second unit operation fluidically connected tothe first unit operation in parallel, and a first bypass conduitfluidically connected to the first unit operation and the second unitoperation in parallel, and a second module fluidically connected to thefirst module in series, the second module comprising a third unitoperation, a fourth unit operation fluidically connected to the thirdunit operation in parallel, and a second bypass conduit fluidicallyconnected to the third unit operation and the fourth unit operation inparallel.

In another aspect, a method for producing chemical products is provided.The method can comprise, in some embodiments, transporting a first fluidcomprising a first chemical reactant through a first module comprising achemical reactor and at least a second unit operation fluidicallyconnected in parallel, and through a second module connected to thefirst module in series, the second module comprising at least oneseparator and at least a fourth unit operation fluidically connected inparallel, such that the first chemical reactant within the first fluidis reacted to form a first chemical product that is transported out ofthe second module, and subsequently, transporting a second fluidcomprising a second chemical reactant through the first module and thesecond module such that the second chemical reactant within the secondfluid is reacted to form a second chemical product, without forming thefirst chemical product, such that the second chemical product istransported out of the second module, wherein no additional unitoperations are newly fluidically connected to the first and secondmodules between the steps of transporting the first fluid andtransporting the second fluid, and no unit operations are fluidicallydisconnected from the first and second modules between the steps oftransporting the first fluid and transporting the second fluid.

In another aspect, a method for the continuous production of aningestible pharmaceutical composition within a reactor system isprovided. The method can comprise, in some embodiments, transporting aninput fluid comprising a chemical reactant through a reactor such thatthe chemical reactant is reacted, within the reactor, to produce anactive pharmaceutical ingredient within a reactor output stream,transporting the reactor output stream to a separator and separating atleast a portion of the active pharmaceutical ingredient from at least aportion of another component of the reactor output stream to produce aseparator product stream having a higher concentration of the activepharmaceutical ingredient than the reactor output stream, andtransporting the separator product stream from the separator to aformulator in which the active pharmaceutical ingredient is convertedinto the ingestible pharmaceutical composition, wherein the amount ofthe active pharmaceutical ingredient within the ingestiblepharmaceutical composition that is output from the formulator is outputat a rate of at least about 20 grams/day, and wherein the reactorsystem, including the reactor, the separator, and the formulator, arecontained within a housing occupying a volume of less than about 100 ft³and/or occupying a footprint of less than about 10 ft².

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention when considered in conjunction with theaccompanying figures. In cases where the present specification and adocument Incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control. If twoor more documents incorporated by reference include conflicting and/orinconsistent disclosure with respect to each other, then the documenthaving the later effective date shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described byway of example with reference to the accompanying figures, which areschematic and are not intended to be drawn to scale. In the figures,each identical or nearly identical component illustrated is typicallyrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention. Inthe figures:

FIG. 1 is a schematic illustration of a system for producing a chemicalproduct, according to one set of embodiments;

FIG. 2A is, according to certain embodiments, a schematic illustrationof a system for producing a chemical product;

FIG. 2B-E are, according to some embodiments, schematic illustrations ofmodules for producing a chemical product;

FIG. 3A-B are schematic illustrations of systems for producing chemicalproducts, according to one set of embodiments;

FIG. 4A is a schematic illustration of an exemplary system for producinga chemical product, according to one set of embodiments;

FIG. 4B is a schematic diagram of the exemplary system illustrated inFIG. 4A.

FIG. 5 is, according to some embodiments, a schematic illustration of anexemplary system for producing a chemical product;

FIG. 6 is a schematic illustration of an exemplary system for producinga chemical product, according to one set of embodiments;

FIG. 7 is a schematic illustration of an exemplary system for producinga chemical product, according to one set of embodiments; and

FIG. 8 is, according to some embodiments, a schematic illustration of anexemplary system for producing a chemical product.

DETAILED DESCRIPTION

Systems and methods related to synthesizing chemical products, includingactive pharmaceutical ingredients, are generally described.

The ability to manufacture chemical products (e.g., activepharmaceutical ingredients (APIs)) in a portable, self-contained, and/orreadily reconfigurable chemical process remains generally elusive. Forexample, chemical synthesis, purification, formulation, and finalpackaging steps typically require large-scale facilities and expensiveoperations. These facilities generally require long timescales todevelop manufacturing methods and to proceed from synthesizing ofchemical products and ingredients to the release of a finished chemical(e.g., pharmaceutical) product. Furthermore, manufacturing delays andshortages can often result when large batches of chemical products failquality control testing. Additionally, the facilities used tomanufacture chemical products are typically designed for themanufacturing of one particular chemical product, and generally requireextensive disassembly and reassembly in order to manufacture additionalchemical products.

Certain of the systems and methods described herein can provide one ormore advantages over traditional chemical (e.g., pharmaceutical)manufacturing systems and methods. Some embodiments described herein maybe used in a variety of applications that can benefit from the abilityto synthesize chemical products in a continuous process. For example, alarge percentage of active pharmaceutical ingredients are typicallyformulated in discrete batch or semi-batch processes. The ability tosynthesize active pharmaceutical ingredients in a continuous manner canallow for a significant reduction in footprints of required facilities,as well as the development of novel synthesis methods. In addition, theuse of continuous flow synthesis in a compact, reconfigurablemanufacturing system can allow for high-throughput, on-demand productionof chemical products (e.g., active pharmaceutical ingredients).

Certain of the embodiments described herein provide tools and relatedtechniques for the synthesis of chemical products (e.g., activepharmaceutical ingredients) in a portable, self-contained system. Forexample, in one set of embodiments, multiple-step chemical processingcan be achieved using a series of modules comprising unit operationsused for chemical synthesis, purification, formulation, and/or finalpackaging of one or more chemical products. In some cases, synthesis oftwo or more chemical products can be achieved without connecting ordisconnecting modules and/or unit operations between the time a firstchemical product is synthesized and the time a second chemical productis synthesized. That is to say, in some embodiments, a first chemicalproduct can be synthesized within the system over a first period oftime, and a second chemical product can be synthesized within the systemat a second period of time that does not overlap with the first periodof time, without the need for fluidically connecting or disconnectingmodules or unit operations between the first and second periods of time.

In addition, chemical products (e.g., active pharmaceutical ingredients)may be synthesized, in some cases, at a high throughput in a system thatoccupies a relatively small footprint. In some embodiments, the processis automated, allowing a user to start an operation and track thesynthesis of chemical products throughout the system. The systems andmethods described herein may be coupled with electronic controls and/orother automation systems to allow for operation without the need forprocess interruptions or shut downs. The systems and methods describedherein, in some embodiments, are portable. In some such embodiments, theportable systems require only an external electrical power supply foreffective operation.

The use of certain of the inventive synthesis systems and methodsdescribed herein offers one or more advantages over typical large-scalebatch systems. Non-limiting examples of such advantages include theability for one user/operator to operate the system, performing multipleunit operations (e.g., one or more reactions, one or more separations,etc.) at the same time at different locations within the sameuninterrupted system. Generally, batch systems would require each unitoperation to be physically and temporally disconnected, requiring muchlonger times, footprints, and workforce requirements, as compared tocertain of the synthesis systems described herein. Additionally, certainof the unit operations described herein can allow for simplification ofchemical synthesis steps (e.g., selecting chemicals to obtain shorterchemical processing sequences, selecting appropriate additives and/orsolvents to yield simplified purification steps, and/or forming chemicalproducts without the need to remove impurities).

In one set of embodiments, systems and methods related to producing oneor more chemical products are described. FIG. 1 includes a schematicillustration of system 100 according to one set of embodiments, whichcan be used to produce one or more chemical products. In someembodiments, the system comprises one or more modules. The module cancontain at least one unit operation. The unit operation can be used toperform a step of a chemical process. In some embodiments, the systemcomprises a plurality of modules connected in series. For example, incertain embodiments, the system comprises a first module and a secondmodule fluidically connected to the first module in series. Referring toFIG. 1, for example, system 100 comprises module 102 and module 104,fluidically connected in series via conduit 114. In some suchembodiments, each of the modules within the series can be used toperform a single step of a multi-step chemical process. For example,referring to FIG. 1, module 102 can be used to perform the first step ina multi-step chemical synthesis process, and module 104 can be used toperform the second step of a multi-step chemical synthesis process.While two modules are illustrated in FIG. 1, additional modules couldalso be used. In some embodiments, the system comprises at least three,at least four, at least five, at least ten, or more modules.

Module 102 may be, according to certain embodiments, configured toreceive a fluid (which may, in some embodiments, comprise a chemicalreactant, a chemical product, and/or a solvent, as described below) viaconduit 110. In some embodiments, module 102 may be configured toreceive an optional additional fluid (which may, in some embodiments,contain a second chemical reactant, a second solvent, etc.) via conduit112. In some such embodiments, module 102 comprises a unit operationconfigured to perform a process that produces one or more output streamshaving a substantially different chemical composition than inputstream(s) 110 and 112, as described in more detail below. As oneexample, in some embodiments, module 102 contains a reactor in which thechemical reactant received via conduit 110 is reacted to form a chemicalreaction product. The output stream produced by module 102 can betransported out of module 102 via conduit 114. In some embodiments,module 104 may be configured to receive the output stream produced bymodule 102 via conduit 114. In some embodiments, module 104 isconfigured to receive an additional fluid via conduit 116. In somecases, module 104 can contain a unit operation that can be configured toperform a process that produces one or more output streams having asubstantially different chemical composition than input stream(s) 114and 116. For example, in some embodiments, module 104 contains a reactorin which a chemical reactant received via conduit 114 is reacted to forma chemical reaction product. As another example, module 104 couldcomprise a separator in which a chemical product received via conduit114 is at least partially separated from another component. The outputstream produced by module 104 can be transported out of module 104 viaconduit 118.

In some embodiments, the system for producing a chemical productcomprises a first module and a second module fluidically connected inseries. By connecting multiple modules in series, one can perform aseries of chemical processing steps as part of an overall chemicalsynthesis process. In some such embodiments, the first module can beused to perform a first step of the chemical synthesis process, and thesecond module can be used to perform a second step of the chemicalsynthesis process.

An exemplary system comprising multiple modules is illustratedschematically in FIG. 2A. In the exemplary embodiment of FIG. 2A, system200 comprises first module 102 fluidically connected in series byconduit 114 to second module 104. First module 102 comprises first unitoperation 220, second unit operation 222 fluidically connected to thefirst unit operation in parallel, and bypass conduit 230 fluidicallyconnected to the first unit operation and the second unit operation inparallel. Second module 104 comprises a third unit operation 286, afourth unit operation 288 fluidically connected to the third unitoperation in parallel, and bypass conduit 290 fluidically connected tothe third unit operation and the fourth unit operation in parallel.

In some embodiments, unit operations and/or bypass conduits arefluidically connected by one or more manifolds. For example, in theexemplary embodiment of FIG. 2A, first unit operation 220, second unitoperation 222, and bypass conduit 230 are fluidically connected bymanifold 210 and manifold 214. In addition, in FIG. 2A, third unitoperation 286, fourth unit operation 288, and bypass conduit 290 arefluidically connected via manifold 280 and manifold 284.

In some embodiments, additional modules can also be included within thesystem. In certain embodiments, additional unit operations and/or bypassconduits can also be fluidically connected to each other within eachmodule. In some embodiments, two or more modules in the system (e.g.,the first module and the second module) comprise identical arrangementsof unit operations.

As introduced above, a module can comprise two or more unit operationsfluidically connected in parallel. For example, in some cases, themodule comprises a first unit operation and a second unit operationfluidically connected to the first unit operation in parallel. Asdescribed herein, a unit operation generally refers to a deviceconfigured to perform a function that produces one or more outputstreams having a substantially different chemical composition than atleast one of the streams input to the unit operation. Generally, anoutput stream has a substantially different chemical composition than aninput stream when the relative abundance of at least one fluid componentwithin the output stream is at least 5 wt % different (or, in somecases, at least 10 wt % different or at least 25 wt % different) thanthe relative abundance of that component in the input stream. The wt %difference of a particular fluid component can be determined bycalculating the absolute value of the difference between the wt % of thefluid component within the output stream and the wt % of the fluidcomponent within the input stream, and dividing the calculated absolutevalue by the wt % of the fluid component within the input stream. Inother words, the wt % difference of a particular fluid component may becalculated as:

${\Delta w} = \frac{{w_{o} - w_{i}}}{w_{i}}$

where Δw is the wt % difference of the particular component, w_(o) isthe wt % of the fluid component within the output stream, and Iv, is thewt % of the fluid component within the input stream.

In some embodiments, more than two unit operations may be fluidicallyconnected in parallel within a module. For example, in some cases, atleast three, at least four, at least five, at least ten, or more unitoperations can be fluidically connected in parallel within a module. Anumber of unit operations may be suitable for use in certain of themodules described herein. Non-limiting examples of unit operationsinclude reactors and non-reactor unit operations (e.g., separators,mixers, etc.), as described in more detail below.

In some cases, the module may comprise at least one bypass conduitfluidically connected to one or more unit operations in parallel. Forexample, in some embodiments, the module comprises a bypass conduit, afirst unit operation, and a second unit operation, wherein each of thebypass conduit, the first unit operation, and the second unit operationare fluidically connected to each other in parallel. The bypass conduitcan include any suitable type of conduit (e.g., a tube, a pipe, achannel, and the like). The bypass conduit generally produces one ormore output streams having a substantially similar chemical compositionas the stream input to the bypass conduit. In some embodiments, thebypass conduit can be used to bypass a unit operation within a module incases where a unit operation does not need to be performed by themodule. For example, if the chemical synthesis process being performedincludes only four steps, and eight modules are provided, fluid may betransported through the bypass conduits of four of the modules that arenot needed to perform the chemical process.

In some embodiments, a module comprises two unit operations and a bypassconduit. As illustrated in the exemplary embodiment of FIG. 2B, module102 comprises two unit operations fluidically connected in parallel. Forexample, exemplary module 102 comprises first unit operation 220 andsecond unit operation 222 fluidically connected to first unit operation220 in parallel. In some embodiments, the module may optionally includemore than two unit operations, as illustrated in FIG. 2C and describedin more detail below. Referring to FIG. 2B, unit operations 220 and 222are fluidically connected via conduits 250 and 252, respectively, toinlet manifold 210 and conduits 260 and 262, respectively, to outletmanifold 214. Module 102 comprises bypass conduit 230 fluidicallyconnected in parallel to first unit operation 220 and second unitoperation 222.

FIG. 2C is an exemplary schematic illustration of a module in which morethan two unit operations are fluidically connected in parallel. In theexemplary embodiment of FIG. 2C, module 102 comprises optional thirdunit operation 224 and optional fourth unit operation 226, eachconnected to first unit operation 220 and second unit operation 222 inparallel. Module 102 in the exemplary embodiment of FIG. 2C alsocomprises bypass conduit 230 fluidically connected in parallel to firstunit operation 220 and second unit operation 222 (and, as illustrated inFIG. 2B, fluidically connected in parallel to third unit operation 224and fourth unit operation 226). Unit operations 224 and 226 arefluidically connected via conduits 254 and 256, respectively, to inletmanifold 210 and conduits 264 and 266, respectively, to outlet manifold214.

Manifolds, as described herein, may comprises a series of pre-connectedconduits, channels, valves, or the like for selecting one or unitoperations in which a fluid and/or fluids may be transported. One ofordinary skill in the art will understand that a valve generally refersto a device which directs and/or controls the flow of a fluid (e.g., byopening or closing a conduit) without fluidically connecting and/ordisconnecting a conduit. Non-limiting examples of valves includemechanical valves, ball valves, check valves, butterfly valves, pistonvalves, pneumatic valves, electronic valves, and hydraulic valves. Insome embodiments, the valve comprises two or more ports (e.g., two portvalves, three port valves, four port valves, etc.).

In certain embodiments, the manifold comprises a plurality of outlets,with each of the plurality of outlets fluidically connected to a singleunit operation or a single bypass conduit within the module. In someembodiments, the manifold(s) within the module can be configured suchthat fluid is selectively transported through a single unit operationwithin the module. In some embodiments, during operation, at least oneof the modules (e.g., at least the first module) is operated such thatat least about 95 wt %, at least about 99 wt %, at least about 99.9 wt%, or substantially all of an input fluid transported into the module istransported through only one of the first unit operation, the secondunit operation, and the bypass (while less than about 5 wt %, less thanabout 1 wt %, less than about 0.1 wt %, or substantially none,respectively, of the input fluid is transported through the remainingfluidic pathways within the module). For example, an operator may, insome cases, select unit operation 220 by choosing an appropriate conduitand/or valve in manifold 210, transporting the fluid from the inlet tomanifold 220 to unit operation 220. In some embodiments, the operatormay select the appropriate conduit and/or valve in manifold 210 suchthat the fluid is transported through bypass conduit 230.

In some cases, a module may comprise an optional second manifold to addan additional optional fluid (e.g., comprising one or more reagentsand/or solvents, as described below) to a selected unit operation. Forexample, referring to FIG. 2D, inlet manifold 210 is fluidicallyconnected to conduit 110 which may, in some cases, transport a fluid(e.g., a first chemical reactant) to one or more unit operationsfluidically connected in parallel. Module 102 may comprise conduit 112to transport a second fluid (e.g., a second chemical reactant) to one ormore unit operations fluidically connected in parallel via inletmanifold 212. Inlet manifold 210 and/or inlet manifold 212 may beconfigured such that one of the unit operations can be selectivelyactivated to perform a step of a chemical process. Alternatively, inletmanifold 210 and/or inlet manifold 212 may be configured such that fluidmay be transported through the bypass conduit. For example, in somecases, a user may select conduit 250 such that a first fluid istransported to unit operation 220 and/or may select conduit 240 suchthat a second fluid is also transported to unit operation 220. In someembodiments, a fluid transported from inlet manifold 210 is mixed (e.g.,with a mixer) with a fluid transported from inlet manifold 212 beforetransporting the fluid to a unit operation.

In some embodiments, transporting the fluid comprises pumping (e.g., viaa pump) the fluid through a conduit, a unit operation, and/or a bypassconduit. It may be advantageous, in some cases, to transport fluidwithout the use of a pump. For example, in may be advantageous, in someembodiments (e.g., where the fluid contains suspended solids), totransport fluid via gravity. One advantage of transporting the fluid viagravity is the prevention of the agglomeration of solids, which couldblock fluid flow within a conduit or unit operation.

As described herein, in some embodiments, at least one of the unitoperations within the module(s) is a reactor. For example, referring toFIG. 2B, in some embodiments, unit operation 220 and/or unit operation222 is a reactor. Referring back to FIG. 2C, in some embodiments, unitoperation 224 and/or unit operation 226 is a reactor. Referring back toFIG. 2B, in some embodiments, reactor 220 is configured to receive aninput stream via conduit 250 comprising a chemical reactant and tooutput a chemical product (e.g., a chemical product, an intermediatechemical product, or an API) to an exit stream via conduit 260. Incertain embodiments, referring now to FIG. 2D, reactor 220 is configuredto receive a first input stream via conduit 250 and a second inputstream via conduit 240, and to output a chemical product to an exitstream via conduit 260.

In general, a reactor comprises a vessel (e.g., a tank, a tube, a coil,a pipe, or the like) configured to perform a chemical reaction. Areactor may be configured, in some cases, to take in a chemical reactant(e.g., from a conduit fluidically connected to a reservoir containingthe chemical reactant, from a conduit fluidically connected to anotherreactor, and/or from a conduit fluidically connected to a non-reactorunit operation) and to produce an intermediate of a target chemicalproduct or to produce the target chemical product itself.

Any suitable type of reactor may be used including, but not limited to,a plug flow reactor, a packed bed reactor (e.g., a catalytic packed bedreactor), a continuously stirred tank reactor, or any other suitablereactor type. For example, in certain embodiments, the reactor comprisesa stainless steel tube, which can be coiled to reduce its size. In someembodiments, the reactor is packed with various materials such as glassor metal beads, sieves and/or resins. In certain embodiments, thereactor comprises a polymer tube (e.g. comprising perfluoroalkoxy (PFA),ethylene tetrafluoroethylene (ETFE), polyether ether ketone (PEEK), orother polymer materials) of defined structures and dimensions (e.g. theinternal diameter), which can be coiled and embedded in a rigid housing(e.g. stainless steel, aluminum, silicon carbide or other rigidmaterials) to ensure (a) heat conduction and (b) high resistance tomechanical stresses under various operating temperatures and pressures.

In some embodiments, the reactor has a relatively small volume. The useof reactors with relatively small volumes can, according to certainembodiments, aid in maintaining the portability of the overall synthesisprocess. In addition, it has been unexpectedly found that small reactorscan be used while maintaining a relatively high reactant throughput.According to certain embodiments, one or more (or all) of the reactorswithin the system has a volume of less than or equal to about 1 liter,less than or equal to about 100 milliliters, less than or equal to about10 milliliters, or less than or equal to about 5 milliliters. In somecases, one or more (or all) of the reactors within the system may be amicroreactor (e.g., wherein the volume of the reactor is less than 1milliliter). In some embodiments, one or more (or all) of the reactorswithin the system has a volume as little as 100 microliters, as littleas 10 microliters, or less.

In some embodiments, the chemical reaction takes place in a continuousmanner, as described below. In some embodiments, the chemical reactionmay take place at a particular volumetric flow rate throughout thereactor. In certain embodiments, the flow rate is a variable flow rate.In some embodiments, the flow rate is a constant flow rate. In someembodiments, the chemical reaction takes place within a reactor at aflow rate ranging between about 1×10⁻⁸ m³/hr to about 1×10⁻⁴ m³/hr. Incertain embodiments, the chemical reaction takes place within a reactorat a flow rate of at least about 1×10⁻⁸ m³/hr, at least about 1×10⁻⁷m³/hr, at least about 1×10⁻⁶ m³/hr, or at least about 1×10⁻⁵ m³/hr.Other flow rates are also possible.

It may be advantageous, in some cases, for a reactor to be operated atan elevated pressure. Operating a reactor at elevated pressures offersseveral advantages as compared to operating a reactor at aboutatmospheric pressure. For example, in certain cases, operating reactorsat elevated pressures can allow one to avoid boiling chemical reagentsand/or solvents (which otherwise might be boiled at atmosphericpressure), which can allow one to perform chemical reactions which wouldnot otherwise occur. In certain cases, operating the reactor at anelevated pressure can increase the reaction rate of the chemicalreaction performed within the reactor. Another advantage to operating areactor at elevated pressures includes removing offending reagents andbyproducts that would otherwise clog the system and/or reduce the yieldof the chemical product. For example, operating a reactor at elevatedpressures may prevent the burning of a product (e.g., throughoverreaction). In some cases, for example, operating reactors atelevated pressures can prevent or reduce the formation of side products,which can remove the need for secondary purification steps betweenmodules and/or unit operations. In some cases, operating a reactor atelevated pressures includes maintaining fluids in an aqueous phase(e.g., enabling a reduction of the volume required to operate thereactor), which may prevent the formation of solids that would otherwiseclog the system.

In some embodiments, the one or more reactors within the system can beoperated at a pressure of between about 15 psi and about 500 psi. Incertain embodiments, the reactor is operated at a pressure greater thanor equal to about 15 psi, greater than or equal to about 50 psi, greaterthan or equal to about 100 psi, greater than or equal to about 150 psi,greater than or equal to about 200 psi, greater than or equal to about250 psi, greater than or equal to about 300 psi, or greater than orequal to about 400 psi. In some embodiments, the system comprises a backpressure regulator (e.g., to regulate the pressure within one or moreunit operations) fluidically connected to one or more unit operations inparallel.

In certain embodiments, the reactor is operated at a relatively hightemperature. Operating the unit operation at high temperatures (e.g.,greater than about 40° C.) can, according to certain embodiments, offera number of advantages. For example, operating a reactor at an elevatedtemperature can accelerate the rate of a chemical reaction performed inthe reactor. In some cases, operating a unit operation at a hightemperature may inhibit or substantially prevent the formation of solidin the reactor (e.g., by operating the unit operation at temperaturesabove the melting point of the solid). In some embodiments, the reactoris operated at a temperature ranging between about 20° C. and about 200°C. In certain embodiments, the reactor is operated at a temperature ofgreater than or equal to about 20° C., greater than or equal to about40° C., greater than or equal to about 60° C., greater than or equal toabout 90° C., greater than or equal to about 100° C., greater than orequal to about 120° C., greater than or equal to about 130° C., greaterthan or equal to about 150° C., or greater than or equal to about 180°C. Other temperature ranges may also be possible.

In certain embodiments, one or more of the unit operations describedherein can be non-reactor unit operations. For example, referring backto FIG. 2A, unit operation 220 can, in some embodiments, be anon-reactor unit operation. Referring again to FIG. 2C, unit operation224 can, in some embodiments, be a non-reactor unit operation. Incertain embodiments, the non-reactor unit operation(s) is fluidicallyconnected to one or more reactor unit operations in parallel. Thenon-reactor unit operation can be any type of unit operation that is nota reactor. For example, in some embodiments, the non-reactor unitoperation is a separator. In certain embodiments, the non-reactor unitoperation is a mixer.

In some embodiments, certain of the unit operations described herein canbe separators. The separators can be used to at least partially separatean intermediate of a target chemical product and/or a target chemicalproduct from at least one other component (i.e., the “removedcomponent”). For example, in some embodiments, the separator can be usedto at least partially separate a target chemical product or anintermediate of the target chemical product from a solvent, a reactionby-product, and/or an impurity. The separator can be configured toremove at least a portion of at least one removed component from aninput stream, without chemically reacting the removed component(s), toproduce a product stream that does not include the removed portion ofthe component. In some embodiments, the removed component can beretained within the separator, as might be observed, for example, in anabsorptive separator. In some embodiments, the removed component can betransported out of the separator in a separate product stream. Forexample, in some cases, the separator may be configured such that afluid stream comprising a target product entering the fluid separatorwill exit the separator in a first exit stream enriched in a targetchemical product, and the removed component exits the separator in asecond exit stream lean in the target chemical product. That is to say,the second exit stream may contain the target chemical product in anamount less than is contained in the feed stream. In some embodiments,the target chemical product comprises a desirable chemical product.

Referring to FIG. 2D, module 102 comprises separator 222. Separator 222can be configured to receive an input stream via conduit 252, which cancontain a chemical reaction product (e.g., a target chemical product oran intermediate of a target chemical product). The chemical reactionproduct can originate, for example, from a reactor upstream of separator222. Separator 222 can be configured to at least partially separate thechemical reaction product from at least one other component of the inputstream (e.g., a solvent). The separation process can result in theproduction of a first exit stream containing the chemical reactionproduct at a concentration greater than the concentration of thechemical reaction product in the input stream. The first exit stream canbe transported via conduit 262 to manifold 214. The separation processcan also result in the production of a second exit stream containingnone of the chemical reaction product or containing the chemicalreaction product at a concentration smaller than the concentration ofthe chemical reaction product in the input stream. The second exitstream can be transported via conduit 268, for example, to a wastecollection unit configured to collect, for example, solvents,byproducts, etc. In some embodiments, transporting a fluid through theseparator results in at least partially separating a chemical productfrom a chemical byproduct. For example, in some embodiments, the inputstream transported via conduit 252 in FIG. 2D contains a chemicalreaction product and a byproduct. In some such embodiments, separator222 is operated such that the first exit stream transported via conduit262 contains the chemical reaction product in a higher concentrationthan the concentration of the chemical reaction product in the inputstream, and the second exit stream transported via conduit 268 containsthe chemical reaction byproduct in a higher concentration than theconcentration of the chemical reaction byproduct in the input stream. Insome embodiments, transporting a fluid through the separator results inat least partially separating a chemical reaction product from asolvent. For example, in some embodiments, the input stream transportedvia conduit 252 in FIG. 2D contains a chemical reaction product and asolvent. In some such embodiments, separator 222 is operated such thatthe first exit stream transported via conduit 262 contains the chemicalreaction product in a higher concentration than the concentration of thechemical reaction product in the input stream, and the second exitstream transported via conduit 268 contains the solvent in a higherconcentration than the concentration of the solvent in the input stream.

In some embodiments, the weight ratio of the chemical product present inthe first exit stream from the separator (e.g., the first exit streamtransported via conduit 262 in FIG. 2D) and the chemical product presentin the second exit stream from the separator (e.g., the second exitstream transported via conduit 268 in FIG. 2D) is at least about 2:1, atleast about 3:1, at least about 5:1, at least about 10:1, at least about50:1, at least about 100:1, or at least about 1000:1. In certainembodiments, the second exit stream from the separator (e.g., the secondexit stream transported via conduit 268 in FIG. 2D) comprisessubstantially none of the target product.

Any of a variety of types of separators may be used in the systems andmethods described herein. In some embodiments, the separator is aliquid-liquid separator. The liquid-liquid separator can be configuredto take in a mixture of a first liquid and a second liquid, and producea first product stream enriched in the first liquid relative to themixture and a second product stream enriched in the second liquidrelative to the mixture. In some embodiments, the liquid-liquidseparator comprises a membrane (e.g., a membrane liquid-liquidseparator). In some embodiments, the separator comprises chemicallyresistant polymeric materials (e.g., polyethylene, high densitypolyethylene (HDPE), PFA, ETFE, polytetrafluoroethylene (PTFE), ultrahigh molecular weight polyethylene (UHMWPE)), a rigid housing (e.g.,stainless steel, aluminum) and the membrane. The membrane, in certainembodiments, may be semipermeable (i.e., the membrane permits thepassage of one or more fluids but excludes the passage of a second fluidthrough the membrane). In the case of certain membrane-based separators,separation can be achieved by relying on the surface tension forcesbetween the membrane, the first fluid in a mixture, and the second fluidin the mixture, as described, for example, in U.S. Patent PublicationNo. 2007/0144967 to Guenther et al. entitled “Fluid Separation” and U.S.Patent Publication No. 2009/0282978 to Jensen et al. entitled“Microfluidic Separators for Multiphase Fluid-Flow Based On Membranes”,each of which is incorporated herein by reference in its entirety forall purposes. In some embodiments, the separator is a reverse osmosisseparator. In certain embodiments, the liquid-liquid separator is aliquid-liquid gravity separator (e.g., a sedimentation liquid-liquidseparator). In certain embodiments, the separator can comprise asettling tank and/or a continuous centrifuge. In some embodiments, theseparator comprises a diaphragm. In certain embodiments, the diaphragmcomprises a chemically resistant polymeric material (e.g., polyethylene,HDPE, PFA, ETFE, PTFE). In some cases, the separator may comprise aself-tuning pressure regulator.

In some embodiments, the separator is a retention column. The retentioncolumn can be configured to retain (e.g., by adsorbing, absorbing, orotherwise taking up) at least one component of a feed stream transportedinto the retention column. In some embodiments, the retention column isa drying column. In certain embodiments, the retention column comprisesan adsorption medium. Non-limiting examples of an adsorption mediuminclude carbon-based material (e.g., charcoal). In some embodiments, thecarbon-based material comprises activated charcoal. Other adsorptionmedia are also possible and those of ordinary skill in the art would beable to select a suitable adsorption medium based on the componentdesired to be removed from the feed stream.

It may be advantageous, in some embodiments, to operate the separator atelevated pressures (e.g., at any of the elevated pressures describedelsewhere herein). For example, operating the separator at elevatedpressures can, in certain embodiments, allow for separation to befollowed immediately by a second high-pressure reaction (e.g.,immediately transporting the separated liquid to a reactor fluidicallyconnected to the separator) without the need to re-pressurize the liquidbefore it enter the second high-pressure reactor.

In some embodiments, a mixer is used as a non-reactor unit operationwithin a module. In certain embodiments, the mixer is fluidicallyconnected to one or more unit operations (e.g., one or more reactorsand/or one or more separators) in parallel. For example, referring toFIG. 2E, unit operation 222 may be a mixer. Mixer 222 may be configured,in some embodiments, to receive a first input stream via conduit 252 anda second input stream via conduit 242, and to output a mixed exit streamvia conduit 262.

Any suitable type of mixer can be used. In some embodiments, the mixercomprises a junction between two or more fluidically connected conduits.In some embodiments, the mixer can be heated (e.g., using a heatexchanger, including any of the types of heat exchangers describedbelow, or others). The fluid can be mixed using static mixers, in someembodiments. In some embodiments, the mixer comprises a stir bar, animpeller, or the like to facilitate mixing of the first input stream andthe second input stream. For example, in certain embodiments, the mixercomprises a Y junction, a T junction, an arrow head, and/or a crossjunction. In some embodiments, the mixer comprises a micromixer and/oran embedded static macromixer. The mixer may be constructed from anysuitable material (e.g., PEEK, PTFE, ETFE, stainless-steel, glass or anyother suitable materials). In certain embodiments, the mixer consists ofa stainless-steel tube packed with glass microbeads (e.g., with anaverage diameter of at least about 100 μm).

In certain embodiments, the module comprises a heat exchanger. In someembodiments, the heat exchanger is fluidically connected (in parallel,or in series) to a unit operation (e.g., a reactor and/or one or morenon-reactor unit operations). Generally, the heat exchanger isconfigured to add heat to and/or remove heat from a fluid within thereactor system. Any suitable type of heat exchanger can be employed. Insome embodiments, the heat exchanger comprises a first fluid configuredto exchange heat with a second fluid (e.g., by contacting a firstconduit comprising the first fluid and a second conduit comprising thesecond fluid). For example, in certain embodiments, the heat exchangeris a double pipe heat exchanger. In some embodiments, the heat exchangeris a shell and tube heat exchanger. In certain embodiments, the heatexchanger is a plate heat exchanger. Other types of heat exchangers arealso possible and will be generally known by those of ordinary skill inthe art. In certain embodiments, the heat exchanger comprises a heater(e.g., an electric heater, a geothermal heater, a solar heater, athermoelectric material (e.g., a Peltier device), and the like). In someembodiments, the heat exchanger comprises a cooling apparatus (e.g., acooling liquid (e.g., a refrigerant or a solvent), a thermoelectricmaterial (e.g., a Peltier device), and the like). In some embodiments,the heat exchanger is configured to transfer heat to and/or remove heatfrom a fluid within the reaction system without the use of a heattransfer fluid. For example, in some embodiments, the heat exchangercomprises a Peltier device, a resistive heating element, and the like.

As mentioned above, certain of the systems described herein can be usedto produce chemical products. Some embodiments comprise transporting afluid (e.g., a chemical reagent, a solvent, or combinations thereof)through the one or more modules fluidically connected in series. Someembodiments comprise transporting a first fluid (e.g., a chemicalreagent, a solvent, or combinations thereof) through a first module anda second module fluidically connected to the first module in series toform a first chemical product (which is output from the second module).

In some such embodiments, the fluid is transported through a unitoperation within the module to perform a step of a multi-step chemicalsynthesis. Some such embodiments comprise producing an exit stream froma module that is compositionally distinguishable from a fluidtransported through an inlet stream of the module. For example, in somecases, a chemical product may be produced in an exit stream of a moduleby performing a reaction within a unit operation within the module. Insome embodiments, the exit stream may be produced by mixing and/orreacting a first fluid and a second fluid in a unit operation. In somecases, the exit stream from the module may be produced by separating, ina unit operation of the module, a first component (e.g., the desiredchemical product) from a second component (e.g., a solvent and/or abyproduct) in a fluid.

In certain embodiments, a module comprises a reactor and is configuredto produce a chemical product (or an intermediate thereof) from achemical reactant. In some such embodiments, the module is configured toreceive a chemical reactant via an inlet, house a chemical reactioninvolving the chemical reactant, and to output a target chemical product(or an intermediate thereof) via an exit conduit. Referring to FIGS. 2Aand 2B, for example, module 102 can be configured to receive an inputstream containing a chemical reactant via conduit 110 and to output astream containing a target chemical compound (or an intermediatethereof) via exit conduit 114.

Any suitable chemical reagent can be used in the systems and methodsdescribed herein. Generally, the type of reagent that is employed in thesystem will depend on the chemical product one wishes to produce. Insome embodiments, the chemical reactant can be a precursor of an activepharmaceutical ingredient. For example, in some embodiments in which onewishes to produce diphenhydramine hydrochloride, dimethylaminoethanolmay be used as a chemical reagent. One such process is described, forexample, in Example 2 below. In certain embodiments in which one wishesto produce lidocaine, 2,6-xylidine may be used as a chemical reagent.One such process is described, for example, in Example 3 below. In someembodiments in which one wishes to produce diazepam,5-chloro-2-methylaminobenzophenone may be used as a chemical reagent. Onsuch process is described, for example, in Example 4 below. In somecases in which one wishes to produce fluoxetine, 3-chloropropiophenonemay be used as a chemical reagent, as described in Example 5 below. Ofcourse, other chemical reagents can also be used including, but notlimited to, dimethylaminoethanol, chlorodiphenylmethane, chloroacetylchloride, ammonia, methylamine, diethylamine, 3-chloropropiophenone,diisobutylaluminium hydride, 4-fluorobenzotrifluoride, and bromoacetylchloride.

In some embodiments, a first fluid comprising a first chemical reactantis transported through a first module. The first module can comprise achemical reactor and at least a second unit operation. The chemicalreactor and the second unit operation can be fluidically connected inparallel. For example, in FIG. 2A, first unit operation 220 can comprisea reactor and can be fluidically connected to unit operation 222 (whichcan be a second reactor or a non-reactor unit operation (e.g., aseparator, a mixer, etc.) in parallel. In some embodiments, the fluidcomprising the chemical reactant is transported through the chemicalreactor within the first module. In some such embodiments, the chemicalreactant is reacted, within the reactor of the first module, to producea chemical product (or an intermediate thereof). In some embodiments,the chemical product is an active pharmaceutical ingredient, asdescribed in more detail below.

Any suitable type of reactor can be used in the first module, includingany of the chemical reactors described elsewhere herein.

In some embodiments, two or more reactors can be fluidically connectedwithin the first module. That is to say, in some embodiments, a firstreactor is fluidically connected in parallel to a second reactor withinthe first module. For example, referring again to FIG. 2A, unitoperation 220 and unit operation 222 may be, in some cases, the firstreactor and the second reactor, respectively. In some such embodiments,the first reactor may be of a first type (e.g., having a first volumeand/or configuration) and the second reactor may be of a second typethat is different from the first type (e.g., having a second volumeand/or configuration different from the first volume and/orconfiguration). Arranging multiple reactors in parallel within a singlemodule can allow one to select a reactor type that is appropriate for agiven chemical product production process.

In certain embodiments, the reactor within the first module isfluidically connected to a non-reactor unit operation in parallel. Asdescribed above, the non-reactor unit operation may be, in some cases aseparator, a mixer, or any other suitable non-reactor unit operation.Referring to FIG. 2A, for example, in some embodiments unit operation222 may be a separator. In some embodiments, unit operation 222 may be amixer. In still other embodiments, unit operation 222 may be a secondchemical reactor, and one or more additional unit operations (not shownin FIG. 2A), such as a mixer and/or a separator, may be fluidicallyconnected to unit operations 220 and 222 in parallel.

Certain embodiments further comprise transporting at least a portion ofthe first fluid (e.g., at least a portion of the fluid output from thefirst module) through a second module fluidically connected to the firstmodule in series. In some embodiments, the second module comprises aseparator and at least one additional unit operation fluidicallyconnected to the separator in parallel. For example, referring to FIG.2A, unit operation 286 can be a separator, which can be fluidicallyconnected to unit operation 288 in parallel. Unit operation 288 can be areactor or a non-reactor unit operation (e.g., a mixer, an additionalseparator, etc.).

Any suitable type of separator can be used in the second module,including any of the separators described elsewhere herein.

In certain embodiments, at least a portion of the fluid transported outof the first module can be transported through the separator of thesecond module. For example, referring to FIG. 2A, the first fluid can betransported into module 102 via conduit 110. Within module 102, areactant within the first fluid can be reacted (e.g., within unitoperation 220, which can be a reactor) to produce a first chemicalproduct (or a precursor of a chemical product). The chemical product canbe transported out of module 102 via conduit 114. In some suchembodiments, at least a portion of the fluid within conduit 114 can betransported to module 104. In some such embodiments, the fluid withinconduit 114 can be transported through a separator within module 104(e.g., unit operation 286, which can be a separator).

In some such embodiments, transporting the fluid through the separatorof the second module results in at least partially removing a solvent.For example, referring to FIG. 2A, in some embodiments, conduit 114comprises a chemical product and a solvent. In some such embodiments,unit operation 286 (which can be a separator) within second module 104can be used to at least partially separate the chemical product from thesolvent. In some such embodiments, at least a portion (or all) of thechemical product can be transported out of second module 104 via conduit118.

In some embodiments, transporting the fluid (e.g., the first fluidand/or the second fluid) through the separator comprises at leastpartially removing an impurity. For example, referring to FIG. 2A, insome embodiments, conduit 114 comprises a chemical product and animpurity. In some such embodiments, unit operation 286 (which can be aseparator) within second module 104 can be used to at least partiallyseparate the chemical product from the impurity. In some suchembodiments, at least a portion (or all) of the chemical product can betransported out of second module 104 via conduit 118.

In some embodiments, transporting the fluid through the separator of thesecond module comprises at least partially separating the fluid into achemical product and a chemical byproduct. For example, referring toFIG. 2A, in some embodiments, conduit 114 comprises a chemical productand a chemical by-product (e.g., produced during the reaction performedin unit operation 220 of module 102). In some such embodiments, unitoperation 286 (which can be a separator) within second module 104 can beused to at least partially separate the chemical product from thechemical by-product. In some such embodiments, at least a portion (orall) of the chemical product can be transported out of second module 104via conduit 118.

In some embodiments, transporting the fluid (e.g., the first fluidand/or the second fluid) through the non-reactor unit operationcomprises heating and/or cooling. In some embodiments, heating and/orcooling the fluid comprises transporting the fluid through a heatexchanger. In certain embodiments, the heat exchanger is fluidicallyconnected to at least one additional unit operation in parallel.

Certain embodiments comprise heating the fluid in a heat exchangerfluidically connected to at least one additional unit operation inparallel. In some embodiments, transporting the fluid through a heatexchanger comprises cooling the fluid.

While two modules are illustrated in FIG. 2A, the system can includeadditional modules, for example, to perform additional steps of amulti-step chemical synthesis. For example, additional modulescontaining reactors may be included upstream or downstream of modules102 and/or 104, to perform additional chemical reaction steps of thechemical synthesis process. As another example, additional modulescontaining additional separators can be included upstream or downstreamof modules 102 and/or 104, to perform additional separation steps.

In some embodiments, the system is configured to produce two or morechemical products. As described above, some embodiments comprisetransporting a first fluid (e.g., a chemical reagent, a solvent, orcombinations thereof) through a first module and a second modulefluidically connected to the first module in series to form a firstchemical product. In some embodiments, after the first chemical producthas been formed, a second fluid comprising a second chemical reactantcan be transported through the first and second modules to form a secondchemical product (which can be transported out of the second module).

In some cases, the system is configured to produce a first chemicalproduct over a first period of time and then a second chemical productover a second period of time. In certain embodiments, the first periodof time does not overlap the second period of time. In some embodiments,the first chemical product can be produced without producing the secondchemical product during the first period of time. In some embodiments,the second chemical product can be produced without producing the firstchemical product during the second period of time. For example, in someembodiments, the system can be operated such that the first chemicalproduct is formed over a first period of time during which time thesecond chemical product is not formed, and the second chemical productis formed over a second period of time during which time the firstchemical product is not formed. In some embodiments, third, fourth,fifth, or more chemical products can be formed during subsequent periodsof time. For example, in some embodiments, the system can be operatedsuch that the first chemical product is formed over a first period oftime (during which time second and third chemical products are notformed), a second chemical product is formed over a second period oftime (during which time the first and third chemical products are notformed), and a third chemical product is formed over a third period oftime (during which time the first and second chemical products are notformed).

In some embodiments, the first chemical product is compositionallydistinguishable from the second chemical product (and/or additionalchemical products that are formed using the system). That is to say, thesecond chemical product can have, in some embodiments, a differentchemical formula than the first chemical product. In some embodiments,the compositionally distinguishable first chemical product and secondchemical product can be formed using an identical set of modulesfluidically connected in series. In certain embodiments, the system isconfigured to produce at least 1, at least 2 at least 3, at least 4, orat least 5 compositionally distinguishable chemical products.

In some embodiments, the system can be configured to form two or more(e.g., at least two, at least three, at least four, at least five, etc.)compositionally distinguishable products without fluidically connectingunit operations to or disconnecting unit operations from the systembetween the formation steps. For example, as described above, someembodiments comprise transporting a first fluid through first and second(and/or more) modules to form a first chemical product, and transportinga second fluid through the first and second (and/or more) modules toform a second chemical product. In some such embodiments, no additionalunit operations are newly fluidically connected to the first and secondmodules between the steps of transporting the first fluid andtransporting the second fluid. In certain such embodiments, no unitoperations are fluidically disconnected from the first and secondmodules between the steps of transporting the first fluid andtransporting the second fluid. That is to say, in some cases, the systemis configured such that a first chemical product and a second chemicalproduct can be produced without adding one or more unit operations toand without removing one or more unit operations from the modules in thesystem.

As one non-limiting example, Examples 2-5 describe the production ofdiphenhydramine hydrochloride, lidocaine, diazepam, and fluoxetine overseparate periods of time between which no unit operations arefluidically disconnected from the synthesis system and no new unitoperations are newly fluidically connected to the synthesis system.

Those of ordinary skill in the art would understand that newlyfluidically connecting a module and/or unit operation to an existingmodule and/or unit operation within a system involves establishing a newphysical fluidic connection (e.g., using a tube, pipe, or other conduit)between the newly-connected module/unit operation and an existingmodule/unit operation within the system. In contrast, newly fluidicallyconnecting a module and/or unit operation to an existing system does notsimply involve switching the position of a fluidic valve such that fluidis re-routed through an already-connected unit operation/module.Similarly, one of ordinary skill in the art would understand thatfluidically disconnecting a unit operation and/or a module from anexisting system involves breaking a physical fluidic connection (e.g.,by removing a tube, pipe, or other conduit) between the unit operationand/or module and the existing system. In contrast, switching theposition of a fluidic valve such that fluid is re-routed away from aunit operation or a module does not constitute fluidically disconnectingthat unit operation or module. Accordingly, in some embodiments, a fluidis transported to one or more unit operations in the system, withoutconnecting or disconnecting unit operations within the system, byselecting an appropriate conduit fluidically connected to a manifold andfluidically connected to one or more unit operations within the module,and routing the fluid to be transported through the desired unitoperation.

The ability to produce multiple chemical products without the need toremove existing fluidic connections and without the need to establishnew fluidic connections can provide a number of advantages, according tocertain embodiments. For example, in some instances, first and secondchemical products (and, in some cases, additional chemical products) canbe produced in a continuous manner without replacing unit operations. Insome embodiments, the amount of time between the synthesis of a firstproduct and the synthesis of a second product can be reduced.

Chemical reactants and/or chemical products can be transported intoand/or out of the modules and/or unit operations in any suitable form.In certain embodiments, one or more of the chemical reactants and/orchemical products transported through the modules and/or unit operationsis in the form of one or more solutes. In certain embodiments, thesolute (e.g., the chemical reactant and/or the chemical product) may bepresent at a relatively high concentration. For example, in someembodiments, a chemical reactant and/or a chemical product may bepresent at a concentration of greater than or equal to about 1 M. Incertain embodiments, a chemical reactant and/or a chemical product maybe present in an amount close to the saturation limit (e.g., within 90%,within 95%, or within 99% of the saturation limit) of the chemicalreactant and/or of the chemical product. As will be understood by thoseskilled in the art, the saturation limit generally refers to theconcentration of a solute before the solute begins to precipitate fromsolution (i.e., form a solid phase of the solute). Several advantages ofusing fluids comprising a high concentration of solutes, as compared tobatch processes where dilute solutes are dissolved and/or suspended in acarrier fluid, include increasing productivity and/or processedmaterials rates and reducing waste and formation of byproducts (e.g.,solid precipitates).

In certain aspects, any of the methods for the production of a chemicalproduct (e.g., an ingestible pharmaceutical composition) describedherein can be continuous processes. In some embodiments, the method forthe continuous production of the chemical product (e.g., the ingestiblepharmaceutical composition) comprises transporting an input fluidcomprising a chemical reactant through a reactor. In certainembodiments, a chemical reactant is reacted, within a reactor, toproduce the chemical product (e.g., an API) within a reactor outputstream. In certain embodiments, the reactor output stream is transportedto a separator fluidically connected to the reactor in series. Forexample, referring to FIG. 3A, a chemical reactant within conduit 110can be transported to module 102, which can contain a reactor. In someembodiments, the chemical reactant from conduit 110 can be reactedwithin the reactor of module 102 to produce a chemical product (e.g., anAPI). Some embodiments comprise separating (e.g., in a separator) atleast a portion of the chemical product (e.g., an API) from at least aportion of another component of the reactor output stream (e.g., asolvent, etc.) to produce a separator output stream having a higherconcentration of the chemical product than the reactor output stream.For example, referring again to FIG. 3A, at least a portion of theoutput stream from the reactor within module 102 can be transported tomodule 104. Module 104 can contain a separator (e.g., as described withrespect to FIG. 2A). In some embodiments, at least a portion of thechemical product within stream 114 can be separated from anothercomponent of stream 114, using the separator within module 104, toproduce an output stream 118, which can contain a higher concentrationof the chemical product than reactor output stream 114.

In some embodiments, the separator product stream is transported fromthe separator to a formulation system, as described below (see, e.g.,formulation system 302 in FIGS. 3A-3B). In some embodiments, theseparator product stream comprises a chemical product (e.g., an API). Insome such embodiments, the chemical product (e.g., API) is a dissolvedsalt.

One of ordinary skill in the art would understand the difference betweena continuous process and a non-continuous process (e.g., a batchprocess). Continuous processes generally refer to systems in whichprecursor enters the system, product exits the system, and thetransformation the system is designed to achieve all occur during atleast a portion of the time during which the transformation occurs. Asone example, in a continuous reactor system, reaction precursor entersthe reactor and reaction product exits the reactor during at least aportion of the time that the chemical reaction within the reactor istaking place. As another example, in a continuous separator, precursorenters the separator and separated product exits the separator during atleast a portion of the time that separation within the separator istaking place. As yet another example, in a continuous crystallizer, atleast partially non-crystallized precursor enters the crystallizer andcrystallized product exits the crystallizer during at least a portion ofthe time that the crystallization process within the crystallizer istaking place.

Continuous systems that include two or more unit operations (e.g.,reactors, separators, and the like) are generally arranged such thattransport between the unit operations within the continuous systemoccurs during at least a portion of the time during which the unitoperations are performing their intended function (e.g., reaction for areactor, separation for a separator, etc.). Continuous systems thatinclude two or more formulation units (e.g., crystallizers, and thelike, as described in more detail below) are generally arranged suchthat transport between the formulation units within the continuoussystem occurs during at least a portion of the time during which theformulation units are performing their intended function (e.g.,crystallizing for a crystallizer, etc.). Continuous systems that includeone or more unit operations and one or more formulation units aregenerally arranged such that transport between the unit operationsand/or the formulation units within the continuous system occurs duringat least a portion of the time during which the formulation units areperforming their intended function. For example, a continuous reactionand separation system might include, for example, a reactor fluidicallyconnected to a separator in which product from the reactor istransported to the separator during at least a portion of the timeduring which reaction within the reactor is taking place and separationwithin the separator is taking place.

In some embodiments, a chemical product is produced continuously from aprecursor of the chemical product when precursor of the chemical productis being transported into the continuous system and chemical product isbeing transported out of the continuous system during at least portionsof the times the components of the continuous system are being operatedto produce the finished chemical product.

One of ordinary skill in the art would be capable of generalizing themeaning of a continuous process to any type of unit operation and/orcombination of unit operations.

In certain embodiments, each unit operation and/or formulation unitwithin the continuous process (e.g., reactor, separator, crystallizer,filter, etc.) is operated in a continuous fashion such that the productsof each unit operation and/or formulation unit are substantiallycontinuously transported from one unit operation and/or formulation unitto the other until the final chemical product is produced. In certainembodiments, at least some of the target chemical product (e.g., atleast about 50 wt %, at least about 75 wt %, at least about 90 wt %, atleast about 95 wt %, or substantially all of the target chemicalproduct) produced by each upstream unit operation and/or upstreamformulation unit within the continuous process is transported to thecorresponding downstream unit operation and/or downstream formulationunit within the continuous process within a period of about 12 hours,about 6 hours, about 1 hour, about 30 minutes, about 10 minutes, about 1minute, or about 10 seconds after it exits the upstream unit operationand/or upstream formulation unit.

In some embodiments, the chemical product is an active pharmaceuticalingredient (API), as discussed in more detail below.

According to certain embodiments, certain of the systems and methodsdescribed herein can be used to produce an ingestible pharmaceuticalcomposition. The ingestible pharmaceutical composition can be producedfrom an API using a formulator, which can contain one or moreformulation units. Referring to FIG. 3A, system 300, in certainembodiments, comprises formulation system 302 fluidically connected toone or more modules (e.g., any of the modules described elsewhereherein) in series. Generally, the formulator is configured to add aningestible component (e.g., an excipient, a binder, etc.) to a mixturecontaining an API and/or to change the phase of the API within themixture containing the API. In some embodiments, the formulator adds aningestible component (e.g., an excipient). In certain embodiments, theformulator converts an active pharmaceutical ingredient to an ingestibleform from a non-ingestible form.

Referring again to FIG. 3A system 300 is an exemplary system comprisingmodule 102, module 104, and formulator 302 fluidically connected inseries. As described herein, in some embodiments, module 102 and/ormodule 104 comprises a unit operation. For example, modules 102 and 104in FIG. 3A can correspond to modules 102 and 104 in FIGS. 1 and/or 2A.In some embodiments, additional modules may also be present.

The method for the production of an ingestible pharmaceuticalcomposition may comprise, in some cases, transporting an input fluidcomprising a chemical reactant through a reactor in module 102 viaconduit 110 such that the chemical reactant is reacted, within thereactor, to produce an active pharmaceutical ingredient within a reactoroutput stream. In certain embodiments, the reactor output stream istransported via conduit 114 to module 104. In some embodiments, module104 comprises a separator. In certain embodiments, the method comprisestransporting the reactor output stream to a separator and separating atleast a portion of the active pharmaceutical ingredient within thereactor output stream from at least a portion of another component ofthe reactor output stream to produce a separator product stream. Incertain embodiments, the separator product stream has a higherconcentration of the active pharmaceutical ingredient than the reactoroutput stream. In certain embodiments, the separator product stream istransported via conduit 118 to formulator 302, in which the activepharmaceutical ingredient is converted into the ingestiblepharmaceutical composition.

In some embodiments, formulator 302 is configured to convert a chemicalproduct (e.g., an API) to an ingestible pharmaceutical composition. Insome embodiments, the ingestible pharmaceutical composition is outputfrom formulation system 302 via conduit 318. Formulator 302 may compriseone or more optional formulation units (e.g., a precipitator, acrystallizer, a dissolution unit, a filter, a mixer, and/or a dryingunit). For example, in some cases, the formulator may comprise aprecipitator. In some embodiments, the formulator comprises two or moreprecipitators (e.g., a first precipitator and a second precipitator). Insome embodiments, the formulator comprises a dissolution unit. Incertain embodiments, the formulator comprises a filter. In someembodiments, the formulator comprises a drying unit. In certainembodiments, the formulator comprises a mixer which can be used, forexample, to mix the API with a pharmaceutically acceptable excipient.Other formulation units are also possible, as described below.

FIG. 3B is a schematic illustration of an exemplary formulator 302,according to certain embodiments. In some embodiments, the formulatorcomprises a precipitator configured to receive a fluid from a modulefluidically connected in series to the precipitator. For example,referring to FIG. 3B, formulator 302 may comprise optional precipitator304. Precipitator may be fluidically connected to one or more modules,for example, positioned upstream of the precipitator. For example, asillustrated in FIG. 3B, optional precipitator 304 may be configured toreceive an input liquid via conduit 320. The input from conduit 320 mayoriginate, for example, from one or more upstream modules. For example,optional precipitator 304 can be located downstream of one or moremodules, such as modules 102 and/or 104 illustrated in FIG. 2A.

In some embodiments, precipitator 304 may be configured to receive asecond fluid via conduit 322. In certain embodiments, converting theactive pharmaceutical ingredient into the ingestible pharmaceuticalcomposition comprises precipitating (e.g., in a precipitator) the activepharmaceutical ingredient from a solution comprising the activepharmaceutical ingredient and a pharmaceutically acceptable carrier.

The precipitator can be configured to facilitate the precipitation of asolid phase from a liquid phase. In certain embodiments, theprecipitator can be configured to facilitate the precipitation of achemical product from a liquid stream containing the chemical product.For example, referring to FIG. 3B, precipitator 304 can receive a liquidinput stream containing a chemical product (e.g., a chemical productformed within a module, such as module 102 and/or 104, located upstreamof the precipitator). Precipitator 304 can be operated such that thechemical product is precipitated within the precipitator to form a solidchemical product.

In certain embodiments, precipitation comprises formation of the solidvia nucleation. Nucleation is a term understood by one of ordinary skillin the art, and is generally used to refer to the beginning of theformation of a solid (e.g., an amorphous solid, a crystalline solid, ora semi-crystalline solid). Nucleation may involve combination ofmaterial (e.g., a dissolved precursor) at the molecular scale to form avery small crystal, for example. It should be understood that crystalsmay exist in many forms, including many polymorphs, solvates andhydrates, for a given crystal material.

In certain embodiments, the precipitator is a crystallizer (e.g., theprecipitated solid is a crystalline solid). In certain such embodiments,converting the active pharmaceutical ingredient into the ingestiblepharmaceutical composition comprises crystallizing (e.g., in acrystallizer) the active pharmaceutical ingredient from a solutioncomprising the active pharmaceutical ingredient and a pharmaceuticallyacceptable carrier. For example, referring again to FIG. 3B, optionalprecipitator 304 may comprise a crystallizer. Any one of a number oftypes of crystallizers can be used. For example, in some embodiments,the crystallizer comprises a cooling crystallizer. As will be understoodby those skilled in the art, a cooling crystallizer generally operatesby decreasing the temperature of a fluid such that solid crystalsprecipitating upon the cooling of the fluid. In some cases, the coolingcrystallizer comprises a mixer. In some embodiments, the crystallizercomprises an anti-solvent crystallization (e.g., an inlet conduitconfigured to be connected to an anti-solvent agent). As will beunderstood by those skilled in the art, anti-solvent crystallizationgenerally refers to the use of one or more solvents which reduce thesolubility of a solute in the fluid. Combinations of the abovecrystallizers (e.g., anti-solvent cooling crystallizers) are alsopossible. Other crystallization methods may also be used and will beknown in the art. Non-limiting examples of additional crystallizationmethods and/or crystallizers include reactive crystallization (e.g.,wherein the reaction between two or more components of a fluid result inthe formation of a solid crystal) melt crystallization (e.g., whereinthe fluid comprises two or more solutes which undergoes crystallizationat the same or at different temperatures), evaporation crystallization(e.g., wherein by varying temperature to increase the concentration of asolute in a fluid a solid crystal may form), and the like. In someembodiments, the crystallizer comprises a polytetrafluoroethylene (PTFE)crystallizer. In certain embodiments, the crystallizer comprises astainless steel crystallizer. Other materials are also possible. Thoseskilled in the art would be able to select an appropriate material foruse as a crystallizer (e.g., a material chemically compatible with oneor more solvents and/or solutions contained within the crystallizer).

In some embodiments, the precipitator comprises a vessel such as a tank.In certain embodiments, the vessel of the precipitator has an internalvolume of between about 100 mL and about 1 L. In some embodiments, thevessel of the precipitator has an internal volume of at least about 100mL, of at least about 250 mL, of at least about 350 mL, of at leastabout 500 mL, or at least about 750 mL. In certain embodiments, theprecipitator has an internal volume of less than about 1 L, less thanabout 750 mL, less than about 500 mL, less than about 350 mL, or lessthan about 250 mL.

In certain embodiments, the precipitation unit comprises a mixer. Anysuitable type of mixer can be used. For example, in some embodiments,the precipitator comprises a impeller which can be used to stir thefluid in the precipitator (e.g., to promote nucleation of a solute). Theimpeller may rotate at any suitable speed. For example, in some cases,the rotational speed of the propeller impeller may be at least about 50rpm, at least about 120 rpm, at least about 200 rpm, at least about 320,or at least about 500 rpm.

The precipitator may be configured to operate, in some cases, at aparticular temperature. For example, the temperature of a fluid in theprecipitator may range between about 0° C. and about 100° C. In someembodiments, the temperature of a fluid in the precipitator may be atleast about 0° C., at least about 3° C., at least about 5° C., at leastabout 10° C., at least about 25° C., or at least about 50° C. In certainembodiments, the temperature of a fluid in the precipitator may be lessthan about 100° C., less than about 50° C., less than about 25° C., lessthan about 10° C., less than about 5° C., or less than about 3° C. Insome embodiments, the temperature with the precipitator and/orcrystallizer is changed during operation. For example, the temperaturemay change (e.g., increase or decrease) at a rate of greater than orequal to about 0.1° C./min.

In some embodiments, a fluid may be added to the precipitator at aparticular flow rate. In certain embodiments, a fluid is added to theprecipitator at a flow rate ranging between about 0.1 mL/min and about 5mL/min. In some cases, for example, the fluid added to the precipitatormay have a flow rate of at least about 0.1 mL/min, at least about 0.3mL/min, at least about 0.5 mL/min, or at least about 2 mL/min. Incertain embodiments, the fluid added to the precipitator may have a flowrate of less than or equal to about 5 mL/min, less than or equal toabout 2 mL/min, less than or equal to about 0.5 mL/min, less than orequal to about 0.3 mL/min.

In certain embodiments, a fluid may remain in the precipitator for agiven amount of time (e.g., a batch time). In some cases, the fluid mayremain in the precipitator for at least about 1 hour, at least about 2hours, at least about 4 hours, at least about 8 hours, or at least about24 hours. In some embodiments, the fluid may remain in the precipitatorfor less than or equal to about 24 hours, less than or equal to about 8hours, less than or equal to about 4 hours, or less than or equal toabout 2 hours.

A variety of solvents can be added to the precipitator (e.g., to controlthe relative saturation of a solute within the precipitator). Exemplarysolvents include, but are not limited to methanol, ethanol, ethylacetate, butyl acetate, isopropyl acetate, propyl acetate, tert-butylacetate, sec-butyl acetate, acetone, isopropanol, and/or combinations ofthese. The anti-solvent can include heptane, isopropyl ether, hexylacetate, isopentyl acetate, pentyl acetate, toluene,4-methyl-2-pentanone, isopropanol, and/or combinations of these.

In certain embodiments, the formulator comprises a filter. For example,referring to FIG. 3B, formulator 302 comprises optional filter 306.Optional filter 306 may be configured to receive an input liquid viaconduit 324. The input from conduit 324 may originate, for example, fromoptional precipitator 304 and/or one or more upstream modules. Forexample, optional filter 306 can be located downstream of optionalprecipitator 304. In some embodiments, optional filter 306 can belocated downstream of one or more modules, such as modules 102 and/or104 illustrated in FIG. 2A.

In some embodiments, filter 306 may be configured to receive a secondfluid via conduit 326. In certain embodiments, converting the activepharmaceutical ingredient into the ingestible pharmaceutical compositioncomprises filtering (e.g., in a filter) a solution comprising the activepharmaceutical ingredient.

The filter can be configured to retain one or more components containedwithin an input stream as the input stream is transported through thefilter. In some embodiments, the filter may perform size-basedfiltration. For example, the filter may include a porous medium that isconfigured to retain material having a cross-sectional dimension thatexceeds a certain cutoff size, while allowing liquids and smaller solidsto pass through. In certain embodiments, the filter may performfiltration based on chemical interactions between the retained componentand the filter. For example, the stream input to the filter may containone or more entities that chemically interact with a medium within thefilter (and, thus, be retained by the filter), while the remainingcomponents of the input may not chemically interact with the medium(and, thus, may be passed through the filter).

In certain embodiments, the filter comprises a membrane. Non-limitingexamples of filter membranes include Hastelloy filtration membranes,polyvinylidene fluoride membranes, polytetrahydrofloride membranes, orothers could be used. In certain embodiments, the average pore sizewithin the membrane modules is between about 0.1 micrometers and about 2micrometers. Those skilled in the art would be able to select anappropriate filter suitable for use in the filter.

In certain embodiments, the filter comprises a dryer. For example, thefilter may comprise a PTFE-dryer. In some embodiments, the filtercomprises a high density polyethylene (HDPE) dryer. Other dryers arealso possible and will be known to those skilled in the art.

In some embodiments the filter may be configured to operate at aparticular temperature (e.g., to evaporate off a solvent). For example,the filter may operate at a temperature ranging between about 40° C. andabout 80° C. In some embodiments, the filter may operate at atemperature of at least about 40° C., at least about 50° C., at leastabout 60° C., or at least about 70° C.

In certain embodiments, the filter may operate under vacuum pressure(e.g., a pressure less than atmospheric pressure). In some embodiments,the vacuum pressure can be maintained at a level suitable to produceeffective filtering. If the vacuum pressure is too low, mother liquorand/or the wash material will not be sufficiently removed, and if thevacuum pressure is too high, the wet cake will be too dry to transfer tosubsequent formulation units.

In some embodiments, a chemical product (e.g., a crystal) may be presentin the filter for a certain amount of time. In certain embodiments, thechemical product may be present in the filter for at least about 10minutes, at least about 1 hour, at least about 2 hours, or at leastabout 4 hours.

In some embodiments, the filter described herein may be configured toallow for extremely fast filtration procedures and multiple washing anddilution steps for a precise control of the purity of thepharmaceutically active ingredient and solid loading of the slurries,which can be important in moving material forward within a continuousintegrated process.

In some embodiments, the system comprises an optional secondprecipitator. The optional second precipitator can be configured toreceive a fluid from a module and/or another formulation unitfluidically connected in series to the second precipitator. For example,referring to FIG. 3B, formulator 302 may comprise optional secondprecipitator 308. Optional precipitator 304 may be fluidically connectedto one or more additional components, such as one or more upstreammodules and/or one or more additional formulation units. For example,referring to FIG. 3B, optional second precipitator 308 may be configuredto receive an input liquid via conduit 330. The input from conduit 328may originate, for example, from one or more upstream modules. In someembodiments, the second precipitator may be a crystallizer. For example,the second precipitator may be any of the crystallizers described above.

In some embodiments, optional second precipitator 308 may be configuredto receive a second fluid via conduit 330. In certain embodiments,converting the active pharmaceutical ingredient into the ingestiblepharmaceutical composition comprises precipitating (e.g., in the secondprecipitator) the active pharmaceutical ingredient from a solutioncomprising the active pharmaceutical ingredient and a pharmaceuticallyacceptable carrier.

In certain embodiments, the formulator comprises an optional secondfilter. For example, referring to FIG. 3B, system 302 comprises optionalsecond filter 310. Optional second filter 310 may be configured toreceive an input liquid via conduit 332. The input from conduit 332 mayoriginate, for example, from optional precipitator 304 and/or one ormore upstream modules. For example, optional second filter 310 can belocated downstream of optional precipitator 304. In some embodiments,optional second filter 310 can be located downstream of one or moremodules, such as modules 102 and/or 104 illustrated in FIG. 2A.

In some embodiments, optional second filter 310 may be configured toreceive a second fluid via conduit 334. In certain embodiments,converting the active pharmaceutical ingredient into the ingestiblepharmaceutical composition comprises filtering (e.g., in a secondfilter) a solution comprising the active pharmaceutical ingredient.

In some embodiments, the formulator comprises a dissolution unit. Forexample, referring to FIG. 3B, system 302 comprises optional dissolutionunit 312. Optional dissolution unit 312 may be configured to receive aninput liquid via conduit 336. The input from conduit 336 may originate,for example, from optional precipitator 304, optional filter 306,optional second precipitator 308, optional second filter 310, and/or oneor more upstream modules. For example, optional dissolution unit 312 canbe located downstream of optional second filter 310. In someembodiments, optional dissolution unit 312 can be located downstream ofone or more modules, such as modules 102 and/or 104 illustrated in FIG.2A.

The dissolution unit may be fluidically connected, in some cases, to thefilter in series. In some embodiments, the dissolution unit isfluidically connected so that it receives at least a portion of theretentate produced by the filter. The dissolution unit can be configuredto dissolve a solute fed to the dissolution within a solvent fed to thedissolution unit. In some cases, the solute may be an activepharmaceutical ingredient.

In some embodiments, converting the active pharmaceutical ingredientinto the ingestible pharmaceutical composition comprises dissolving(e.g., in a dissolution unit) the active pharmaceutical ingredient in apharmaceutically acceptable excipient, such as a pharmaceuticallyacceptable carrier.

The dissolution unit can be used, for example, to dilute the filteredproduct formed in the filter, for example, to make the filtered productmore flowable, and therefore, more suitable for use in a continuousmanufacturing process. The dissolution unit can include any suitableunit such as, for example, a tank or other suitable chamber in whichproduct can be diluted (e.g., using solvents, as described herein).Examples of units suitable for use in the dissolution unit, for example,include dilution tanks.

In some embodiments, the formulator comprises one or more additionalformulation units. For example, referring to FIG. 3B, formulator 302comprises additional optional formulation unit 314. Optional formulationunit 314 is, in certain embodiments, configured to receive an inputliquid via conduit 340. In some such embodiments, optional formulationunit 314 is configured to output an ingestible pharmaceuticalcomposition via conduit 318.

In some embodiments, a diluted stream output from the dissolution unitcan be transported to the additional optional formulation unit (e.g.,via conduit 340 in FIG. 3B). The additional optional formulation unitcan be used to form an ingestible product from an upstream productcontaining an active pharmaceutical ingredient. The additional optionalformulation unit can include a variety a components to form aningestible pharmaceutical composition. For example, referring to FIG.3B, additional optional formulation unit 314 might include an extruderor other powder handling system used to produce tablets, ingestiblepowders, capsules, injectable solution or suspension, or any othersuitable form of ingestible pharmaceutical composition. In certainembodiments, the additional optional formulation unit can include acoater, for example, to produce coated tablets and/or capsules. In someembodiments, the additional optional formulation unit is a mixer, asdescribed above. After processing by the additional optional formulationunit, ingestible pharmaceutical compositions (e.g., tablets, capsules,injectable solutions and/or suspensions, etc.) can be transported fromthe system. In certain embodiments, additional optional formulation unit314 may be configured to produce an ingestible pharmaceuticalcomposition and dispense the ingestible pharmaceutical composition viaconduit 318.

In some embodiments, the one or more formulation units in the formulatormay be configured to receive an additional fluid (e.g., a second fluid).For example, referring to FIG. 3B, in some embodiments, precipitator 304may be configured to receive a second fluid via conduit 322. In certainembodiments, filter 306, crystallizer 308, filter 310, dissolution unit312, and/or additional formulation unit 314 may be configured to receivea second fluid via conduits 326, 330, 334, 338, and/or 342,respectively. The second fluid may comprise, in some cases, a solvent,an excipient, and/or a binder, as described herein. In some embodiments,precipitator 304, filter 306, crystallizer 308, filter 310, dissolutionunit 312, and/or additional formulation unit 314 are configured tooutput a non-ingestible component from a pharmaceutical-containingmixture via conduits 326, 330, 334, 338, and/or 342, respectively.

In one specific embodiment, formulator 302 comprises multipleformulation units that are fluidically connected in series. Referring toFIG. 3B, the system may comprise, in some cases, six optionalformulation units, fluidically connected in series. In some suchembodiments, system 302 comprises, precipitator 304, filter 306,crystallizer 308, filter 310, dissolution unit 312, and additionalformulation unit 314 fluidically connected in series. Precipitator 304,filter 306, crystallizer 308, filter 310, dissolution unit 312, andformulator 314 may be optional, according to certain embodiments. Inother embodiments, formulator 302 comprises a subset of the one or moreformulation units fluidically connected in series (e.g., one optionalformulation unit, two optional formulation units, three optionalformulation units, four optional formulation units, or five optionalformulation units). For example, in certain embodiments, formulator 302comprises precipitator 304, filter 306, and dissolution unit 312. Insome embodiments, formulator 302 comprises crystallizer 308, filter 310,and dissolution unit 312. In some such embodiments, precipitator 304 maybe fluidically connected to filter 306 in series, and in some suchembodiments, precipitator 304 and filter 306 are bypassed andcrystallizer 308, filter 310 and dissolution unit 312 are fluidicallyconnected to one or more modules, such as modules 102 and/or 104illustrated in FIG. 2A.

In some embodiments, the fluid transported through a module and/or aformulation unit, as described above, comprises a solvent. Non-limitingexamples of suitable solvents include water, inorganic salt aqueoussolutions (e.g., sodium chloride, potassium chloride, ammonium chloride,and ammonium acetate), isopropanol, ethanol, methanol, hexane, heptane,toluene, ethyl acetate, diethyl ether, tert-butyl methyl ether, dioxane,tetrahydrofuran, chloroform, dichloroethane, dichloromethane,N-methyl-2-pyrrolidone, N,N-dimethylformide, N,N-dimethylacetamide,dimethyl sulfoxide, hydrochloric acid, acetone, sodium hydroxide(aqueous solution), or combinations thereof. Other solvents are alsopossible. Those skilled in the art would be capable of selecting anappropriate solvent.

In some embodiments, the systems described herein may be contained,and/or the methods described herein may be conducted, within a housing.As will be understood by those skilled in the art, a housing generallyrefers to a frame that at least partially encloses a piece of equipment.The housing can be any suitable material. Non-limiting examples ofhousing materials include steel, iron, aluminum, plastic (e.g.,polyacrylic, polycarbonate, polyethylene, polystyrene), glass, and/orwood. In some embodiments, the housing is open (i.e., the housingcomprises one or more openings on one or more sides of the housing). Incertain embodiments, the housing is closed.

In some embodiments, the housing within which synthesis systemsdescribed herein are contained occupies a relatively small volume. Forexample, in some embodiments, the housing within which the synthesissystems described herein are contained, while the system is assembled ina functional form, occupies a volume of less than about 100 ft³ or lessthan about 50 ft³. In some embodiments, the housing within which thesynthesis systems described herein are contained, while the system isassembled in a functional form, occupies a footprint of less than about10 ft² or less than about 5 ft². The use of systems with relativelysmall volumes and/or relatively small footprints can provide a number ofadvantages, according to certain embodiments. For example, in someembodiments, the compact nature of the system can make it relativelyportable, allowing for the production of pharmaceuticals or otherchemical products at multiple locations.

In some embodiments, the housing contains a system assembled infunctional form comprising a first module comprising at least two unitoperations fluidically connected to each other in parallel, a secondmodule comprising at least two unit operations fluidically connected toeach other in parallel, and a formulator, wherein the housing occupies avolume of less than about 100 ft³ or less than about 50 ft³. In someembodiments, the housing contains a system assembled in functional formcomprising a first module comprising at least two unit operationsfluidically connected to each other in parallel, a second modulecomprising at least two unit operations fluidically connected to eachother in parallel, and a formulator, wherein the housing occupies afootprint of less than about 10 ft² or less than about 5 ft². In somesuch embodiments, the formulator within the housing comprises at leastone dissolution unit, at least one precipitator, at least one filter,and at least one mixer. In some such embodiments, the formulator withinthe housing comprises at least one dissolution unit, at least twoprecipitators, at least two filters, and at least one mixer.

As noted above, certain of the systems and methods described herein canbe used to synthesis an active pharmaceutical ingredient (“API”). Asused herein, the term “active pharmaceutical ingredient” (also referredto as a “drug”) refers to an agent that is administered to a subject totreat a disease, disorder, or other clinically recognized condition, orfor prophylactic purposes, and has a clinically significant effect onthe body of the subject to treat and/or prevent the disease, disorder,or condition. Active pharmaceutical ingredients include, withoutlimitation, agents listed in the United States Pharmacopeia (USP),Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10thEd., McGraw Hill, 2001; Katzung, B. (ed.) Basic and ClinicalPharmacology, McGraw-Hill/Appleton & Lange, 8th edition (Sep. 21, 2000);Physician's Desk Reference (Thomson Publishing); and/or The Merck Manualof Diagnosis and Therapy, 17th ed. (1999), or the 18th ed (2006)following its publication, Mark H. Beers and Robert Berkow (eds.), MerckPublishing Group, or, in the case of animals, The Merck VeterinaryManual, 9th ed., Kahn, C. A. (ed.), Merck Publishing Group, 2005.Preferably, though not necessarily, the active pharmaceutical ingredientis one that has already been deemed safe and effective for use in humansor animals by the appropriate governmental agency or regulatory body.For example, drugs approved for human use are listed by the FDA under 21C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporatedherein by reference; drugs for veterinary use are listed by the FDAunder 21 C.F.R. §§ 500 through 589, incorporated herein by reference.All listed drugs are considered acceptable for use in accordance withthe present invention.

In certain embodiments, the active pharmaceutical ingredient is a smallmolecule. Exemplary active pharmaceutical ingredients include, but arenot limited to, anti-cancer agents, antibiotics, anti-viral agents,anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents,steroidal or non-steroidal anti-inflammatory agents, antihistamine,immunosuppressant agents, antigens, vaccines, antibodies, decongestant,sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics,hormones, prostaglandins, etc.

As used herein, the term “small molecule” refers to molecules, whethernaturally-occurring or artificially created (e.g., via chemicalsynthesis) that have a relatively low molecular weight. Typically, asmall molecule is an organic compound (i.e., it contains carbon). Thesmall molecule may contain multiple carbon-carbon bonds, stereocenters,and other functional groups (e.g., amines, hydroxyl, carbonyls, andheterocyclic rings, etc.). In certain embodiments, the molecular weightof a small molecule is at most about 1,000 g/mol, at most about 900g/mol, at most about 800 g/mol, at most about 700 g/mol, at most about600 g/mol, at most about 500 g/mol, at most about 400 g/mol, at mostabout 300 g/mol, at most about 200 g/mol, or at most about 100 g/mol. Incertain embodiments, the molecular weight of a small molecule is atleast about 100 g/mol, at least about 200 g/mol, at least about 300g/mol, at least about 400 g/mol, at least about 500 g/mol, at leastabout 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, orat least about 900 g/mol, or at least about 1,000 g/mol. Combinations ofthe above ranges (e.g., at least about 200 g/mol and at most about 500g/mol) are also possible.

Non-limiting examples of APIs include diphenhydramine, lidocaine,diazepam, fluoxetine, ibuprofen, doxycycline, and atropine. Those ofordinary skill in the art, given the present disclosure, would becapable of applying the synthesis methods and systems described hereinto other pharmaceutical active ingredients.

Also as noted above, certain of the systems and methods described hereincan be used to produce ingestible pharmaceutical compositions.Generally, ingestible pharmaceutical compositions refer to thosecompositions including an active pharmaceutical ingredient and apharmaceutically acceptable excipient. As used herein, the term“pharmaceutically acceptable excipient” means a non-toxic, inert solid,semi-solid or liquid filler, diluent, encapsulating material orformulation auxiliary of any type. Some non-limiting examples ofmaterials which can serve as pharmaceutically acceptable excipients aresugars such as lactose, glucose, and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose,ethyl cellulose, and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients such as cocoa butter and suppository waxes;oils such as peanut oil, cottonseed oil; safflower oil; sesame oil;olive oil; corn oil and soybean oil; glycols such as propylene glycol;esters such as ethyl oleate and ethyl laurate; agar; detergents such asTween 80; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; water (e.g., pyrogen free water); isotonicsaline; citric acid, acetate salts, Ringer's solution; ethyl alcohol;and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

In some embodiments, the ingestible pharmaceutical composition comprisesat least about 2.5 mg, at least about 5.0 mg, or at least about 20 mg ofan active pharmaceutical ingredient per milliliter of a pharmaceuticallyacceptable carrier. In some embodiments, the active pharmaceuticalingredient is dissolved in the pharmaceutically acceptable carrier. Incertain embodiments, the active pharmaceutical ingredient is suspendedin the pharmaceutically acceptable carrier. In certain embodiments, theingestible pharmaceutical composition is in the form of a tablet, apill, or a liquid.

In some embodiments, the system is configured to produce at least about1000 doses of API per day. In certain embodiments, the system isconfigured to produce at least about 2000 doses per day, at least about4000 doses per day, at least about 8000 doses per day, at least about10000 doses per day, or at least about 20000 doses per day. As will begenerally understood by one skilled in the art, the term dose generallyrefers to an amount of an active pharmaceutical ingredient and/or drugproduct which is administered to an organism (e.g., a person, an animal,a plant, an insect, and/or a bacterium) to stimulate a biologicalresponse. In certain embodiments, the system is configured to produce atleast about 20 grams/day, at least about 50 grams/day, at least about100 grams/day, at least about 200 grams per day, or at least about 400grams per day of a chemical product (e.g., an ingestible pharmaceuticalcomposition).

In certain embodiments, the system is configured to produce a relativelyhigh amount of an active pharmaceutical ingredient in a small footprint.For example, in some cases, the system may be configured to produce atleast about 5 grams of an active pharmaceutical ingredient per squarefoot footprint area per day. In some embodiments, the system isconfigured to produce at least about 7 g/day/ft², at least about 10g/day/ft², at least about 20 g/day/ft², at least about 30 g/day/ft², atleast about 50 g/day/ft², at least about 60 g/day/ft², at least about 70g/day/ft², at least about 90 g/day/ft², at least about 100 g/day/ft², atleast about 120 g/day/ft², at least about 150 g/day/ft², or at leastabout 200 g/day/ft² of an active pharmaceutical ingredient per day perfootprint area. In certain embodiments, the system is configured toproduce at least about 1 gram of an active pharmaceutical ingredient percubic feet of a housing (e.g., as described above) per day. For example,in some embodiments, the system is configured to produce at least about2 g/day/ft³, at least about 3 g/day/ft³, at least about 4 g/day/ft³, atleast about 5 g/day/ft³, at least about 7 g/day/ft³, at least about 10g/day/ft³, at least about 15 g/day/ft³, at least about 20 g/day/ft³, orat least about 25 g/day/ft³ of an active pharmaceutical ingredient pervolume of a housing per day.

The following examples are intended to illustrate certain embodiments ofthe present invention, but do not exemplify the full scope of theinvention.

Example 1

This example describes a system in which modules containing various unitoperations were arranged in series to perform multiple chemicalreactions, according to certain embodiments. Examples 2-5 demonstratethe use of the exemplary system illustrated in FIG. 4A to producediphenhydramine hydrochloride, lidocaine, diazepam, and fluoxetinethrough the selection of appropriate modules and unit operations and/orbypasses.

As described in more detail below, to produce a chemical product, a unitoperation (e.g., a reactor or a non-reactor unit operation) or bypasswas selected in each module to produce the desired sequence of unitoperations for a particular chemical synthesis process. Referring toFIG. 4A, System 400 can be operated such that one can switch between onechemical synthesis process (e.g., a process to manufacturediphenhydramine hydrochloride) and another chemical synthesis process(e.g., a process to manufacture lidocaine) simply by actuating one ormore valves (e.g., in a manifold) to reroute existing fluidicconnections, as opposed to disconnecting existing unit operations and/orconnecting new unit operations to the chemical synthesis system.

System 400 comprised five modules (420, 440, 460, 470, and 480 in FIG.4A) fluidically connected in series. System 400 also comprised 10reservoirs (401, 402, 403, 404, 405, 406, 407, 408, 409, and 410 in FIG.4A), which were configured to hold the chemical reagents and solventsused to perform the chemical synthesis processes. System 400 alsocomprised precipitator 492, filter 493, crystallizer 495, filter 496,dissolution unit 497, and formulator 499 fluidically connected inseries. Precipitator 492 was fluidically connected in series to module480. The system occupied a footprint of 0.315 m² and a volume of 0.551m³. FIG. 4B is a schematic diagram of exemplary system 400.

Module 420 was configured to receive a fluid from reservoirs 401, 402,and 403 via conduits 411, 412, and 413, respectively. Conduits 412 and413 were joined at conduit 416, fluidically connected to manifold 421.Conduit 411 was fluidically connected to conduit 422 to optionally addan additional fluid to the input stream to unit operation 423.

Module 420 comprised 10 mL reactor 423, 5 mL reactor 426, 30 mL reactor429, and bypass conduit 431, fluidically connected in parallel bymanifold 421 and manifold 432. Manifold 421 was used to select one ormore of reactor 423, reactor 426, reactor 429, via conduit 422, conduit425, and conduit 428, respectively, and/or bypass conduit 431, toperform a desired step of a chemical synthesis process. Conduit 424,conduit 427, and conduit 430 were fluidically connected and configuredto output a fluid (e.g. a chemical product) from reactor 423, reactor426, and reactor 429, respectively, to manifold 432. Module 440 wasfluidically connected in series to module 420 via conduit 433, and wasconfigured to receive one or more fluids from module 420, reservoir 404via conduit 414 and/or from reservoir 405 via conduit 415. Conduit 414and conduit 415 were fluidically connected to conduit 445 and conduit448, respectively.

Module 440 comprised liquid-liquid membrane separator 443, 10 mL reactor446, 30 mL reactor 449, and bypass conduit 451 fluidically connected inparallel by manifold 441 and manifold 452. The liquid-liquid separatorcomprised wetted parts in chemically resistant polymeric materials(e.g., PFA, ETFE, PTFE) a rigid housing (e.g. stainless steel, aluminum,other suitable materials) and a semi-permeable membrane. Theliquid-liquid separator had a footprint of about 0.05 ft². Thesemi-permeable membrane was a PTFE membrane with an average pore size ofabout 0.5 microns. The separator also comprised a self-tuning pressureregulator comprising PFA (approximately 0.002 inches in thickness). Thereactors comprised an internal tubular polymeric coil of definedstructure and dimensions embedded in a rigid aluminum housing. Manifold441 was used to select one or more of separator 443, reactor 446,reactor 449, via conduit 442, conduit 445, and conduit 448,respectively, and/or bypass conduit 451, to perform a desired step of achemical synthesis process. Conduit 444, conduit 447, and conduit 450were fluidically connected and configured to output a first fluid (e.g.,a chemical product) from separator 443, reactor 446, and reactor 449,respectively, to manifold 452. Conduit 453 was fluidically connected toseparator 443 and was configured to remove a second fluid from separator443.

Module 460 was fluidically connected in series to module 440 via conduit455, and was configured to receive one or more fluids from module 440,reservoir 406 via conduit 456, and/or reservoir 407 via conduit 457.

Module 460 comprised mixer 464 and bypass conduit 462 fluidicallyconnected in parallel by manifold 461 and manifold 466. Manifold 461 wasused to select one or more of mixer 464 via conduit 463 and/or bypassconduit 462, to perform a desired step of a chemical synthesis process.Conduit 456 and conduit 457 were fluidically connected to mixer 464.Conduit 465 was fluidically connected and configured to output a fluid(e.g., a chemical product) from mixer 464 via conduit 465 to manifold466.

Module 470 was fluidically connected in series to module 460 via conduit467, and was configured to receive one or more fluids from module 460,reservoir 408 via conduit 458, and/or reservoir 409 via conduit 459.Conduit 458 and conduit 459 were fluidically connected to conduit 467.

Module 470 comprised separator 474 and bypass conduit 472 fluidicallyconnected in parallel by manifold 471 and manifold 476. Manifold 471 wasused to select one or more of separator 474 via conduit 473 and/orbypass conduit 472, to perform a desired step of a chemical synthesisprocess. Conduit 475 was fluidically connected and configured to outputa first fluid (e.g., a chemical product) from separator 474 via conduit475 to manifold 476. Conduit 477 was fluidically connected to separator474 and was configured to remove a second fluid from separator 474.

Module 480 was fluidically connected in series to module 470 via conduit491 and was configured to receive one or more fluids from module 470and/or reservoir 410 via conduit 490. Conduit 491 was fluidicallyconnected to conduit 478 which was fluidically connected to manifold476, and to conduit 490.

Module 480 comprised separator 484 and bypass conduit 482 fluidicallyconnected in parallel by manifold 481 and manifold 486. Manifold 481 wasused to select one or more of separator 484 via conduit 483 and/orbypass conduit 482, to perform a desired step of a chemical synthesisprocess. Conduit 485 was fluidically connected and configured to outputa first fluid (e.g., a chemical product) from separator 484 via conduit485 to manifold 486. Conduit 488 was fluidically connected to separator484 and was configured to remove a second fluid from separator 484.Conduit 487 was fluidically connected to manifold 486. Precipitator 492was fluidically connected in series to module 480 via conduit 487.Precipitator 492 was a HDPE precipitator with a maximum volume of 400mL.

The fluid was transported from precipitator 492 to filter 493, tocrystallizer 495, to filter 496, to dissolution unit 497, and toformulation unit 499 fluidically connected in series. The final chemicalproduct (e.g., an ingestible pharmaceutical composition) was output fromconduit 498.

As described in more detail below, appropriate reservoirs and unitoperations were selected in the system to produce one or more chemicalproducts. The same system was used for each chemical synthesis, asdescribed below, without fluidically connecting and/or fluidicallydisconnecting a conduit, a module, a unit operation, or a reservoir.

For illustration purposes, only the modules used in the formation oflidocaine, diazepam, and diphenhydramine chloride are shown in FIG. 4A.It should be noted that module 420, module 440, module 460, module 470,and module 480, as well as precipitator 492, filter 493, crystallizer495, filter 496, dissolution unit 497, and formulation unit 499 havebeen simplified for illustration purposes and may comprise one or moreadditional unit operations (e.g., reactors and/or non-reactor unitoperations), one or more additional conduits, and/or one or moreadditional manifolds, not shown. In some embodiments, conduit 487 wasfluidically connected to one or more additional modules and/or aformulator. In system 400, conduit 487 was fluidically connected toprecipitator 492. Those skilled in the art would readily appreciate thatthe synthesis of one or more additional chemical products (e.g., APIs)could also be performed with this system with or without the one or moreadditional components not illustrated here.

Referring to FIG. 4A, Table 1 summarizes the unit operations selected ineach module for the synthesis of diphenhydramine hydrochloride,lidocaine, and diazepam. Referring to FIG. 4A, Table 2 summarizes thecontents of each reservoir for the synthesis of diphenhydraminehydrochloride, lidocaine, and diazepam.

TABLE 1 Diphenhydramine Module Hydrochloride Lidocaine Diazepam 420 10mL reactor 423 10 mL reactor 423 10 mL reactor 423 (at 180° C.) (at 120°C.) (at 90° C). 440 Bypass conduit 451 30 mL reactor 449 10 mL reactor446 (at 130° C.) (at 130° C.) 460 Mixer 464 Bypass conduit 462 Bypassconduit 462 470 Separator 474 Separator 474 Separator 474 480 Bypassconduit 482 Bypass conduit 482 Separator 484

TABLE 2 Diphenhydramine Reservoir Hydrochloride Lidocaine Diazepam 401Dimethylamino- 2,6-Xylidine 5-Chloro-2-(methyl- ethanol (1.43M in NMP)amino)benzophenone (1M in NMP) 402 N-Methyl-2- N-Methyl-2- pyrrolidinonepyrrolidinone (NMP) (NMP) 403 Chlorodiphenyl- Chloroacetyl Bromoacetylchloride methane chloride 404 Et₂NH (1.5M in MeOH) KOH (0.5M in H₂O) 405Ammonia solution (3.5M in MeOH:H₂O, 9:1 mixture) 406 NaOH aqueoussolution (3M) 407 Hexane 408 Hexane Ethyl acetate 409 NaCl/NH₄Cl 20%NaCl aqueous aqueous solution solution (20 wt % each) 410 HCl aqueoussolution (4M)

Example 2

This example describes the continuous synthesis and formulation ofdiphenhydramine hydrochloride using system 400, illustrated in FIG. 4Aand described in Example 1. Here, module 420 was selected to use a 10 mLreactor, module 440 was selected to use bypass conduit 451, module 460was selected to use mixer 464, module 470 was selected to use separator474, and module 480 was selected to use bypass conduit 482, as outlinedin Table 1 and described in more detail, below. The synthesis ofdiphenhydramine hydrochloride is further illustrated in FIG. 5. It isimportant to note that no modules, unit operations, and/or conduits werefluidically connected and/or disconnected to the system between thesynthesis of diphenhydramine hydrochloride and lidocaine (Example 3),diazepam (Example 4), or fluoxetine (Example 5). That is to say, no newmodules, unit operations, or conduits were added to the system and nomodules, unit operations, or conduits were removed from the system. Somemodules, unit operations, and/or conduits utilized in this example arenot illustrated in FIG. 4A for simplification purposes, but aredescribed herein.

Referring again to FIG. 4A, 10 mL reactor 423 was selected to reactchlorodiphenylmethane with 2-dimethylaminoethanol at 180° C. under apressure of 250 psi. It should be noted that the reaction was completewithin 15 minutes, as compared to a batch process (e.g., 125° C. inbenzene for a similar substrate) in which the reaction was completed ingreater than five hours. An excess of 2-dimethylamino-ethanol was usedto carry the quaternary ammonium salt through reactor 423. 3 M ofaqueous sodium hydroxide, preheated to 140° C., was injected afterreactor 423 via conduit 456 to quench hydrochloric acid. The extractionof crude diphenhydramine was performed after a back pressure regulator(BPR) by concomitant injection of hexane and water, to remove anyremaining 2-dimethylaminoethanol. The diphenhydramine was then passedthrough a short packed-bed column to improve extraction efficiency (seealso FIG. 5) fluidically connected to conduit 467, and the organic phasewas separated from the aqueous waste via the selection of agravity-operated liquid-liquid separator 474. Crude diphenhydramine (82%yield) in hexane was then conveyed, after filtration through activatedcharcoal, to precipitator 492 for further processing and formulation.

It should be noted that the combination of an excess of2-dimethylaminoethanol and high temperatures (i.e. temperatures greaterthan the melting point of the quaternary ammonium intermediate) allowedto keep the processed material flowing in the tubular reactor.

The first step in the downstream process was the precipitation of thecrude diphenhydramine (e.g., a crude freebase solution) withhydrochloric acid to form a salt. Approximately, 300 mL of the crudefreebase solution was pumped into precipitator 492 and cooled to 10° C.Hydrochloric acid solution in diethyl ether (0.5M) was then added at arate of 0.5 mL/min while stirring at 200 rpm until a 1:1 molar ratio wasobtained. After the addition of the acid was complete, the slurry wasstirred for one hour. The precipitated salt was filtered through filter493, which comprised a HDPE-based dryer with a Hastelloy filtrationmembrane. The filtered material was washed with 100 mL of cold hexaneand then dried in the same unit under vacuum at room temperature for onehour. The dried crude salt was then dissolved in isopropanol at 60° C.so that the concentration was 196.5 mg/mL. The counter-current flow ofpre-heated isopropanol at high pressures permitted the transport oflarge quantities of diphenhydramine salt that would otherwise have notbeen easily performed. The solution was then crystallized incrystallizer 495 comprising a HDPE crystallizer equipped with apropeller type impeller rotating at 120 rpm. Controlled crystallizationof diphenhydramine from isopropanol was achieved because as the solutionis hot, isopropanol acts as a solvent, yet on cooling, it becomes ananti-solvent. It would not typically be expected that such a solutioncould flow and/or that isopropanol would serve as a good anti-solvent.The solution was cooled at 1° C./min to a final temperature of 5° C. Theslurry obtained was then filtered and dried in a filter 496 with adrying temperature of 70° C. The purified and dried crystals were thendissolved in water to yield a concentrate in dissolution tank 497. Theconcentrate was then diluted to a final dosage concentration of 2.5mg/mL in formulation tank 499. One dose of liquid this liquidformulation is 5.0 ml at a concentration of 2.5 mg/mL. The purity of thefinal dosage form was measured using HPLC and conformed to the USPstandard.

Example 3

This example describes the continuous synthesis and formulation oflidocaine using system 400, illustrated in FIG. 4A and described inExample 1. Here, module 420 was selected to use 10 mL reactor 423,module 440 was selected to use 30 mL reactor 449, module 460 wasselected to use bypass conduit 462, module 470 was selected to useseparator 474, and module 480 was selected to use bypass conduit 482, asoutlined in Table 1 and described in more detail, below. The synthesisof lidocaine is further illustrated in FIG. 6.

The production of lidocaine consisted of a consecutive 2-step synthesisand a 1-step post-synthetic extraction/separation, all in one continuousflow, as further illustrated in FIG. 6. The first step of synthesis wasthe direct amidation of 2,6-xylidine with chloroacetyl chloride inN-methyl-2-pyrrolidinone (NMP) in 10 mL reactor 423 at 120° C. Thetime-dependent decomposition of chloroacetyl chloride inN-methyl-2-pyrrolidinone (NMP) was avoided by mixing streams of bothchemicals to form a solution in situ. Upon amidation, a mixture of KOHand diethylamine was introduced to quench HCl generated from prior stepand form the tertiary amine moiety in lidocaine. The mixture was addedat a temperature of 130° C. (well above the boiling point ofdiethylamine (55° C.) and several other solvents (methanol and water))to 30 mL reactor 449. The reaction was complete within 5 minutes (ascompared to a batch reaction which required greater than 60 minutes inrefluxing toluene or 4-5 hours in refluxing benzene).

The optimal ratio of MeOH and H₂O was critical to dissolve all theintermediates, side-products and final product. The two reactionsrequired 22.4 minutes to reach complete conversion (99%, according toHPLC) from 2,6-xylidine to lidocaine. It should be noted that theamidation between 2,6-xylidine and chloroacetyl chloride through the useof a polar solvent NMP allowed for short reaction times at unusuallyhigh concentrations, resulting in high productivity that would nottypically be expected within a small footprint.

In order to deliver relatively pure lidocaine solution to the downstreamoperations and to keep purification as simple as possible, a highlyefficient extraction was designed. A mixed sodium and ammonium chlorideaqueous solution (2 mL/min) and hexane (3 mL/min) was injected into theoutgoing stream (1.65 mL/min) through a cross junction of conduits 459and 467. The inclusion of a packed-bed column fluidically connected toconduit 467 (see also FIG. 6) with borosilicate beads increased masstransfer, and crude lidocaine in hexane was obtained upon in-linegravity liquid-liquid separation in separator 474. Thesynthesis/purification sequence was monitored in real-time via in-lineinfrared spectroscopy. Steady state was reached after 60 minutes andabout 90% yield of lidocaine was obtained and delivered to thedownstream unit, as a 0.11 M solution in hexane (3 mL/min).

Precipitation was performed in precipitator 492 at 10° C. with apropeller impeller stirred at 320 rpm. Once 250 mL of crude solution hasentirely been pumped into the precipitation unit, 82.5 mL of 0.5 M HClin diethyl ether was added at a flow rate of 0.1 mL/min. The molar ratioof HCl to crude was 1.5:1. Lidocaine hydrochloride was obtained after 8h holding time with a yield of about 95% and a purity of 93.6%.

The slurry was then drained into filter 493. After the mother liquor(ML) was filtered, the crystals were washed with 250 mL of hexane whilefiltering the ML. Once the washing liquid (WL) was filtered, theproduced filter cake was dried under vacuum in the filter at 50° C. for60 min.

Recrystallization was then performed in crystallizer 495 using anantisolvent (e.g., hexane) cooling crystallization process (cooling from50° C. to 5° C.) with a holding time of 2 h at 5° C. A mixture ofacetone/isopropanol (96:4) was used as the solvent. Hexane (40 vol %)was added with a flow rate of 2 mL/min at 50° C. while cooling down with1° C./min. The crystallizer was stirred with a propeller impeller at 200rpm. The initial concentration was 34.6 mg/mL. After 2 h of holding timeat 5° C., a yield of 87.6% with a purity of 97.7% was achieved.

The purified crystals were next drained into filter 496. After the MLwas filtered, the crystals were washed with 100 mL of hexane (pumpedinto the crystallizer) while filtering the ML. Once the WL was filtered,the filter cake was dried under vacuum at 50° C. for 120 min in filter496. Once the drying was finished, 50 mL of a premixed solutioncomprising 4% sodium carboxymethyl cellulose in water was added tore-suspend and dissolve the crystals with a stirring rate of 200 rpm indissolution unit 497. The solution was drained into formulation tank499.

The concentration was verified employing an ultrasound probe and thenwas be diluted to a final dosage of 20 mg/mL.

Example 4

This example describes the continuous synthesis and formulation ofdiazepam using system 400, illustrated in FIG. 4A and described inExample 1. Here, module 420 was selected to use 10 mL reactor 423,module 440 was selected to use 10 mL reactor 446, module 460 wasselected to use bypass conduit 462, module 470 was selected to useseparator 474, and module 480 was selected to use separator 484, asoutlined in Table 1 and described in more detail, below. The synthesisof diazepam is further illustrated in FIG. 7.

The synthesis for the production of diazepam involved a three-stepcontinuous process, as further illustrated in FIG. 7. 10 mL reactor 423and 10 mL reactor 446 were selected, operated at 90° C. and 130° C.,respectively. Bromoacetyl chloride was utilized instead of chloroacetylchloride in order to prevent the clogging of reactor 446 and henceensure a high output in diazepam, enabling highly efficientamination/intramolecular imine formation at low water ratio(MeOH/H₂O=9:1) without causing extensive salt formation. Under optimalconditions, conversion of starting materials reached greater than 95%,producing diazepam at 78% yield (HPLC). Analysis of the crude mixturerevealed several side products, including starting5-chloro-2-(methylamino)benzophenone intermediate halides, and theirhydrolysis adducts and as well as dimers/trimers.

It should be noted that diazepam is generally poorly soluble in water,and moreover, the synthesis of diazepam in two consecutive stepsgenerates several different salts that are poorly soluble in organicsolvents. The use of optimal reagents (e.g., bromoacetyl chloride) andoptimal solvent combinations (e.g., water, NMP, and/or MeOH) permittedthe production of diazepam in one continuous flow without clogging ofthe system. Additionally, the reaction was conducted at 130° C. in 10 mLreactor 446, well above the boiling point of ammonia (−33° C.) andseveral other solvents used in the process (e.g., methanol and water).The reaction was complete within five minutes (as compared to a batchprocess with required greater than 24 hours in methanol for similarsubstrates).

The subsequent continuous purification setup was designed to efficientlyremove all side products and impurities, some of which having verysimilar properties (e.g., solubility, pKa, etc.) with diazepam itself.The purification setup combined three consecutive stages consisting ofextractions and filtrations. A first continuous extraction of thereaction mixture with aqueous sodium chloride (20 wt.-%) and ethylacetate separated diazepam from water soluble side-products generated inthe process Then, the acetyl acetate extract was passed through acartridge fluidically connected to conduit 467 and loaded with activatedcharcoal to remove dark colored by-products (e.g. dimers and trimers).At this point, an in-line silicon infrared (IR) probe was inserted forreal-time monitoring. Finally, a continuous extraction with aqueous HCl(4 M) was performed, separating organic impurities (in ethyl acetate)from the conjugated acid of diazepam (in water). The continuousseparation was carried out using gravity-based liquid-liquid separators.The process delivered diazepam hydrochloride in water (0.1 M) that wasconveyed to the next module for advanced purification.

Precipitation was performed in precipitator 492 at 10° C. with apropeller impeller stirred at 320 rpm. Once 250 mL of crude solution wasentirely pumped into the precipitator, 93 mL of 28% aqueous ammoniumhydroxide was added with a flow rate of 0.3 mL/min. The overall holdingtime was 24 h with a yield of about 95% and a purity of 96.7%. Theslurry from the precipitator was drained into filter 493. After themother liquor (ML) was filtered, the crystals were washed with 250 mL ofwater (pumped into the precipitator) while filtering the ML. Once thewashing liquid (WL) was filtered, the resultant filter cake was driedunder vacuum at 50° C. for 60 min in filter 493. The recrystallizationwas conducted in crystallizer 495 using an antisolvent (water)crystallization at 25° C. with a holding time of 2 h anddimethylsiloxane (DMSO) as solvent. Water (70 vol %) was added with aflow rate of 2 mL/min. The crystallizer was stirred with a propellerimpeller at 200 rpm. The initial concentration produced was 21.6 mg/mL.After 2 h of holding time at 25° C., diazepam was obtained in 93.6%(104.3% purity). Next, the slurry was drained into filter 496. After theML was filtered, the crystals were washed with 100 mL of water (pumpedinto the crystallizer) while filtering the ML. Once the WL was filtered,the resultant filter cake was dried under vacuum at 60° C. for 240 minin filter 496. After drying, 40 mL of ethanol was added to re-suspendand dissolve the crystals with a stirring rate of 200 rpm in dissolutionunit 497. When the solution was drained into formulation tank 499, theconcentration was measured using ultrasound to be 7.83 mg/mL and thenadjusted by the operator to the final dose concentration of 5.263 mg/mL.The operator could also dilute the concentrated diazepam/ethanolsolution with water to obtain the final dose concentration of 1 mg/mL(comprising 19 vol % Ethanol).

Example 5

This example describes the continuous synthesis and formulation offluoxetine using the system described in Example 1. As described below,reactors, unit operations, and bypasses were selected from system 400(FIG. 8) to perform the appropriate reaction steps.

It is important to note that no modules, unit operations, and/orconduits were fluidically connected and/or disconnected to the systembetween the synthesis of fluoxetine and diphenhydramine hydrochloride(Example 2), lidocaine (Example 3), or diazepam (Example 4). That is tosay, no new modules, unit operations, or conduits were added to thesystem and no modules, unit operations, or conduits were removed fromthe system. Some modules, unit operations, and/or conduits utilized inthis example are not illustrated in FIG. 4A for simplification purposes,but are described herein. For example, the synthesis and formulation offluoxetine utilized system 400 as illustrated in FIG. 4A, by selectingfour reactors, four separators, a heat exchanger, and a molecular sieve,fluidically connected but not shown in FIG. 4A.

Key challenges overcome included the ability to perform reactionsin-line for forward chemical compatibility (pressurized liquid/liquidextractions, 250 psi), efficiency of extractions, precise control of theinternal fluid pressure (single chamber multi-inlet pressure regulatorsto enable liquid/liquid extractions with membrane separators), dealingwith solid formation (Aluminates, KOH, KF), presence of water inreaction solvents, retarded rates of reaction (presence of toluene infinal step), and obtaining the crude API as a solution directlytransferable and usable for downstream processing.

The continuous flow synthesis of fluoxetine, as illustrated in moredetail in FIG. 8, started with a DIBAL (1 M in toluene) reduction of3-chloropropiophenone (3 M in toluene) carried out in 5 mL spiralreactor (Reactor I in FIG. 8). 3-chloropropiophenone was close tosaturation. The reduction proceeded smoothly at room temperature andreached completion within 10 min at 0.36 mmol/min scale (96% yield).

Aluminum salts were not compatible with the subsequent aminationreaction, thus requiring removal; however, their quench (4 M HCl, aq.)generated copious amounts of solids. An ultrasonic transducer enabledfast dissolution of the salts and hence continuous operation. Atwo-stage in-line extraction and separation sequence was implementedwith successive membrane liquid-liquid separators (SEPm I and II, FIG.8) for removing aqueous waste and gas from DIBAL decomposition. A secondstream of aqueous 4 M HCl was injected in the system before SEPm IIallowing for complete quench. The intermediate alcohol was obtained in91% yield post-separation.

The intermediate alcohol (0.75 M in the main toluene stream) was thendirected to reactor III (FIG. 8) where it reacted with aqueousmethylamine (11.5 M, 15 equivalents). Segmented-flow conditions allowedfor fast transfer of methylamine from the aqueous droplets towardtoluene and also solvation of ammonium salts. The conversion of thestarting alcohol reached 93% after 10 min of residence time in a 10 mLspiral reactor set at 140° C. (89% yield). The reaction temperature of140° C. is well above the boiling point of methylamine (and close to thecritical point of methylamine) and several of the solvents used (e.g.,methanol and toluene). The reaction was completed within 10 minutes.

The third separation step was especially challenging due to contrastingneeds of the extraction in view of the subsequent SN_(Ar) reaction. Poorsolubility of the desired aminoalcohol in toluene and formation of anemulsion at the reactor outlet precluded efficient in-line separation(33% yield after extraction), while the SNAr was particularly dependenton use of water-miscible, polar solvents where hydrophobic solventshighly hampered reactivity. As such, tetrahydrofuran (THF) was used asan extraction solvent. By ionizing the aqueous layer with sodiumchloride (20 wt.-%), THF became water-immiscible, efficiently extractingthe aminoalcohol (90% after in-line separation), while not posing ahindrance to the aromatic substitution. Other solvents were investigatedsuch as diethyl ether, dimethoxyethane, dimethylsulfoxide (DMSO),dimethylformamide (DMF), and sulfolane which either failed to extractthe intermediate aminoalcohol or caused clogging.

Though the extraction was efficient, H₂O solubility in THF wasnon-negligible, and the coexistence of water and potassium tert-butoxideled to precipitation of KOH and clogging in reactor IV. Selection of amolecular sieve in the seventh module (MS, 4 Å, FIG. 8) circumventedthis outcome.

Just upstream of reactor IIV (10 mL, 140° C.), the dried and preheatedstream of aminoalcohol came into contact with consecutive streams ofpotassium tert-butoxide/18-Crown-6, 0.25 M and 0.05 M in DMSO,respectively, and 4-fluorobenzotrifluoride in DMSO (0.24 M), yieldingcrude fluoxetine.

Just downstream reactor IV, a stream of water was injected before theBPR to avoid precipitation of potassium fluoride and other salts, andprevent clogging of the BPR. The main effluent was then extracted by astream of tert-butyl methyl ether (TBME) and the organic phase wasseparated from the aqueous waste via a final gravity-operatedliquid-liquid separator. Crude fluoxetine in TBME was then conveyed witha flow rate of 4.6 mL/min and a concentration of 7.5 mg/mL from theupstream to the downstream unit for further processing and formulation.Precise control of pressure regulation was an important consideration.

Precipitation was performed at 3° C. with a propeller impeller stirredat 320 rpm in precipitator 492. The precipitator was loaded with about50 mg of fluoxetine HCl seed crystals before the crude solution waspumped. Once 300 mL of crude solution was pumped into the precipitator,10 mL of 2 M HCl solution in diethyl ether was added at a flow rate of0.5 mL/min. Then, 60 mL of hexane (antisolvent) was added with a flowrate of 0.5 mL to lower the solubility of fluoxetine hydrochloride inthe solution. The resulting slurry was allowed to remain in solution forat least 8 hours. The precipitated salt was then filtered using aspecially constructed filter/dryer unit made of HDPE with a Hastelloyfiltration membrane and washed with 250 mL of hexane in filter 493. Oncethe washing liquid (WL) was filtered, the resulting filter cake is driedunder vacuum at 50° C. for 60 min in filter 493.

The dried crude salt was then dissolved in acetone at 50° C., and thesolution was crystallized in crystallizer 495 in a HDPE crystallizerequipped with a PTFE propeller type impeller rotating at 120 RPM. Therecrystallization was performed in a two stage antisolvent (hexane)cooling crystallization process (cooling from 50° C. to 5° C.) with aholding time of 2 h at 5° C. Hexane (37.5%) was added at 50° C. andcooled down at 1° C./min. The concentration in stage one was 26.3 mg/mLand 21.2 mg/mL in stage two. The average yield of both stages was 74%with a purity of 93.0 and 102.0%, respectively.

The resulting slurry was then filtered and dried in filter 496 at 70° C.The purified and dried crystals were then dissolved in water to yield aconcentration of 4 mg/mL in dissolution unit 497. With such formulation,5 mL represents one dose, i.e. 20 mg of fluoxetine hydrochloride. Thepurity of the final dosage form was measured using HPLC and conformed tothe USP standard.

Example 6

Table 3 summarizes the dosage and rate of synthesis of the system usedfor the synthesis of diphenhydramine, lidocaine, diazepam, andfluoxetine, as described in Examples 2-5.

Typically, a single 1000 gram batch production of lidocaine wouldrequire about 500 liters of hexane and at least a 1000 liter batchreactor (e.g., for the liquid-liquid extraction/separation steps). Incontrast, the system described herein sustained the separation of 1000grams of lidocaine with a compact continuous liquid-liquid separator ina complete system occupying a footprint of approximately 0.551 m³ (551liters).

TABLE 3 diphen- hydramine lidocaine diazepam fluoxetine g/day 439 225195 22 dosage (mg) 20 100 10 10 doses/day 21,950 2,250 19,500 2,200kg/year 160 82 71 8 doses/year 8,011,750 821,250 7,117,500 803,000g/day/m² 1,394 714 619 70 g/day/m³ 796 408 354 40 doses/day/m² 69,6837,143 61,905 6,984 doses/day/m³ 39,819 4,082 35,374 3,991

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,and/or methods, if such features, systems, articles, materials, and/ormethods are not mutually inconsistent, is included within the scope ofthe present invention.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Other elements may optionallybe present other than the elements specifically identified by the“and/or” clause, whether related or unrelated to those elementsspecifically identified unless clearly indicated to the contrary. Thus,as a non-limiting example, a reference to “A and/or B,” when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A without B (optionally including elements other thanB); in another embodiment, to B without A (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” and the like are to be understoodto be open-ended, i.e., to mean including but not limited to. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, Section 2111.03.

What is claimed is: 1-29. (canceled)
 30. A method for producing chemicalproducts, comprising: transporting a first fluid comprising a firstchemical reactant through a first module comprising a chemical reactorand at least a second unit operation fluidically connected in parallel,and through a second module connected to the first module in series, thesecond module comprising at least one separator and at least a fourthunit operation fluidically connected in parallel, such that the firstchemical reactant within the first fluid is reacted to form a firstchemical product that is transported out of the second module; andsubsequently, transporting a second fluid comprising a second chemicalreactant through the first module and the second module such that thesecond chemical reactant within the second fluid is reacted to form asecond chemical product, without forming the first chemical product,such that the second chemical product is transported out of the secondmodule; wherein: no additional unit operations are newly fluidicallyconnected to the first and second modules between the steps oftransporting the first fluid and transporting the second fluid, and nounit operations are fluidically disconnected from the first and secondmodules between the steps of transporting the first fluid andtransporting the second fluid.
 31. The method of claim 30, whereintransporting the first fluid through the separator comprises separatingthe first fluid into a first stream containing the first chemicalproduct and a second stream containing a first chemical byproduct. 32.The method of claim 30, wherein the first and/or second chemicalproducts is an active pharmaceutical ingredient (API).
 33. The method ofclaim 32, wherein the API is diphenhydramine, lidocaine, diazepam,and/or fluoxetine.
 34. The method of claim 32, wherein the API isprocessed downstream into a tablet, a pill, or a liquid.
 35. The methodof claim 30, wherein the first and/or second chemical product containsat least about 2.5 mg of the API per milliliter suspended in apharmaceutically acceptable carrier. 36-37. (canceled)
 38. The method ofclaim 30, wherein the reactor has a volume of less than or equal toabout 1 L. 39-41. (canceled)
 42. The method of claim 30, wherein the atleast one reactor is operated at a pressure of greater than or equal toabout 200 psi.
 43. The method of claim 30, wherein the at least onereactor is operated at a temperature of greater than or equal to about60° C. 44-45. (canceled)
 46. A method for the continuous production ofan ingestible pharmaceutical composition within a reactor system,comprising: transporting an input fluid comprising a chemical reactantthrough a reactor such that the chemical reactant is reacted, within thereactor, to produce an active pharmaceutical ingredient within a reactoroutput stream; transporting the reactor output stream to a separator andseparating at least a portion of the active pharmaceutical ingredientfrom at least a portion of another component of the reactor outputstream to produce a separator product stream having a higherconcentration of the active pharmaceutical ingredient than the reactoroutput stream; and transporting the separator product stream from theseparator to a formulator in which the active pharmaceutical ingredientis converted into the ingestible pharmaceutical composition, wherein theamount of the active pharmaceutical ingredient within the ingestiblepharmaceutical composition that is output from the formulator is outputat a rate of at least about 20 grams/day, and wherein the reactorsystem, including the reactor, the separator, and the formulator, arecontained within a housing occupying a volume of less than about 100 ft³and/or occupying a footprint of less than about 10 ft².
 47. The methodof claim 46, wherein the housing occupies a footprint of less than about10 ft².
 48. The method of claim 46, wherein the housing occupies avolume of less than about 100 ft³. 49-50. (canceled)
 51. The method ofclaim 46, wherein the active pharmaceutical ingredient isdiphenhydramine, lidocaine, diazepam, and/or fluoxetine.
 52. The methodof claim 46, wherein the ingestible pharmaceutical composition is atablet, a pill, or a liquid.
 53. The method of claim 46, wherein thereactor has a volume of less than or equal to about 1 L. 54-56.(canceled)
 57. The method of claim 46, wherein the reactor is operatedat a pressure of greater than or equal to about 200 psi.
 58. The methodof claim 46, wherein the reactor is operated at a temperature of greaterthan or equal to about 60° C. 59-60. (canceled)
 61. The method of claim46, wherein the separator product stream is transported from theseparator to a formulator comprising a precipitator, a filter, adissolution tank, and/or an additional formulation unit.
 62. (canceled)63. The method of claim 46, wherein converting the active pharmaceuticalingredient into the ingestible pharmaceutical composition comprises:precipitating the active pharmaceutical ingredient from a solutioncomprising the active pharmaceutical ingredient and a pharmaceuticallyacceptable solvent, and/or crystallizing the active pharmaceuticalingredient from a solution comprising the active pharmaceuticalingredient and a pharmaceutically acceptable solvent, and/or dilutingthe active pharmaceutical ingredient with a pharmaceutically acceptablesolvent. 64-66. (canceled)
 67. The method of claim 46, wherein thereactor output stream and/or separator product stream is transportedwithout a pump.